U.S. patent application number 09/999506 was filed with the patent office on 2002-10-03 for inorganic shaped bodies and methods for their production and use.
This patent application is currently assigned to Vita Special Purpose Corporation. Invention is credited to Dychala, David H., Erbe, Erik M., Sapieszko, Ronald S..
Application Number | 20020140137 09/999506 |
Document ID | / |
Family ID | 38135805 |
Filed Date | 2002-10-03 |
United States Patent
Application |
20020140137 |
Kind Code |
A1 |
Sapieszko, Ronald S. ; et
al. |
October 3, 2002 |
Inorganic shaped bodies and methods for their production and
use
Abstract
Shaped, preferably porous, inorganic bodies are provided which
are prepared from a reactive blend. In accordance with one
preferred embodiment, the solution is absorbed into a porous
sacrificial substrate such as a cellulose sponge. The
solution-saturated substrate is heated and an oxidation-reduction
reaction occurs thereby forming an inorganic solid. A shaped,
inorganic body is formed in situ. Optional, but preferred
additional thermal treatment of the shaped, inorganic body removes
the organic substrate, leaving an inorganic body that faithfully
mimics the porosity, shape, and other physical characteristics of
the organic substrate. Inorganic substrates may also be used to
good effect. Large varieties of shaped bodies can be prepared in
accordance with other embodiments of the invention and such shapes
find wide use in surgery, laboratory and industrial processes and
otherwise. The invention also provides chemically and
morphologically uniform powders, including those having uniformly
small sizes.
Inventors: |
Sapieszko, Ronald S.;
(Woodbury, MN) ; Dychala, David H.; (West Chester,
PA) ; Erbe, Erik M.; (Berwyn, PA) |
Correspondence
Address: |
Woodcock Washburn LLP
46th Floor
One Liberty Place
Philadelphia
PA
19103
US
|
Assignee: |
Vita Special Purpose
Corporation
|
Family ID: |
38135805 |
Appl. No.: |
09/999506 |
Filed: |
November 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09999506 |
Nov 15, 2001 |
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09253556 |
Feb 19, 1999 |
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60117254 |
Jan 26, 1999 |
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Current U.S.
Class: |
264/629 |
Current CPC
Class: |
A61F 2250/0058 20130101;
C04B 2111/00836 20130101; A61F 2002/30535 20130101; A61B 17/80
20130101; C04B 28/34 20130101; C04B 28/34 20130101; A61B 17/866
20130101; C04B 2103/0067 20130101; C04B 41/46 20130101; C04B
2103/0067 20130101; C04B 22/085 20130101; C04B 38/0051 20130101;
C04B 32/00 20130101; C04B 22/16 20130101; C04B 22/064 20130101;
C04B 35/447 20130101; C04B 38/0074 20130101; Y10T 428/2982
20150115; C04B 38/0025 20130101; A61F 2/2875 20130101; A61F 2/32
20130101; C04B 32/00 20130101; C04B 28/34 20130101; C04B 38/0025
20130101; C04B 2111/0081 20130101; A61C 8/0012 20130101; C04B
38/009 20130101; A61P 19/00 20180101; C04B 2111/00793 20130101;
A61F 2/28 20130101; A61B 17/72 20130101; C04B 32/00 20130101; A61L
27/12 20130101; Y10S 977/906 20130101; C04B 38/0025 20130101; C04B
2103/0067 20130101; C04B 35/447 20130101; C04B 38/08 20130101; C04B
38/08 20130101; C04B 38/0615 20130101; C04B 41/46 20130101; C04B
38/0615 20130101; C04B 22/085 20130101; C04B 38/0074 20130101; C04B
41/46 20130101; C04B 38/0615 20130101; C04B 38/0074 20130101; C04B
38/0615 20130101; C04B 38/0615 20130101; C04B 40/0263 20130101;
C04B 38/0051 20130101; C04B 40/0028 20130101; C04B 22/16 20130101;
C04B 38/08 20130101; C04B 22/064 20130101; C04B 38/08 20130101;
C04B 40/0263 20130101; C04B 40/0028 20130101; C04B 40/0028
20130101; C04B 40/0263 20130101; C04B 41/46 20130101; C04B 40/0028
20130101; C04B 38/0074 20130101; C04B 40/0263 20130101; C04B
38/0051 20130101; C04B 2103/0067 20130101; C04B 38/0051 20130101;
C04B 38/0615 20130101 |
Class at
Publication: |
264/629 |
International
Class: |
C04B 033/32 |
Claims
What is claimed is:
1. A method for preparing an inorganic material comprising: a.
imbibing a substrate with a reactive blend comprising: at least one
metal cation; at least one oxidizing agent; and at least one
precursor anion oxidizable by said oxidizing agent to form an
oxoanion; b. reacting said reactive blend while imbibed by the
substrate to initiate an oxidation-reduction reaction between said
oxidizing agent and the precursor anion; c. said reaction evolving
at least one gaseous product, giving rise to said oxoanion and
forming the inorganic material.
2. The method of claim 1 wherein the substrate has a preselected
shape.
3. The method of claim 2 wherein said inorganic material assumes
the shape and morphology of the substrate.
4. The method of claim 1 wherein said oxidizing agent is
nitrate.
5. The method of claim 1 wherein said gaseous product is a nitrogen
oxide.
6. The method of claim 1 wherein said heating step is conducted at
temperatures of up to about 250.degree. C.
7. The method of claim 1 wherein said heating step is conducted at
temperatures of up to about 800.degree. C.
8. The method of claim 1 wherein said heating step is conducted at
temperatures of up to about 1400.degree. C.
32. The method of claim 1 wherein said inorganic material has a
pore volume of at least about 90%.
33. The method of claim 1 wherein said inorganic material has a
pore volume of at least about 92%.
34. The method of claim 1 wherein said inorganic material has a
pore volume of at least about 94%.
35. The method of claim 1 wherein said inorganic material has a pre
volume of at least about 70% together with macro-, meso-, and
microporosity.
36. The method of claim 1 wherein said inorganic material has a pre
volume of at least about 90% together with macro-, meso-, and
microporosity
37. The method of claim 1 wherein said substrate is in a
preselected shape and the inorganic material is formed in an
approximation of that shape.
38. The method of claim 37 wherein said shape is a tube, block or
sphere.
39. The method of claim 37 wherein said shape is in the form of a
human bone, mammalian bone, or vertebra.
40. The method of claim 37 wherein said shape is hollow.
41. The method of claim 37 wherein said shape is machined.
42. A method for preparing an inorganic material comprising: a.
imbibing onto the surface of an organic substrate a reactive blend
comprising: at least one metal cation; at least one oxidizing
agent; and at least one precursor anion oxidizable by said
oxidizing agent to form an oxoanion; b. conducting an initial
heating step to react said reactive blend while imbibed in the
organic substrate under conditions of temperature and pressure
effective to initiate an oxidation-reduction reaction between said
oxidizing agent and the precursor anion; c. said reaction evolving
at least one gaseous product, giving rise to said oxoanion and
forming the inorganic material; and d. performing a subsequent
heating step of said inorganic shaped body to remove any residue of
said organic substrate.
43. The method of claim 42 wherein the organic substrate has a
preselected shape.
44. The method of claim 42 wherein the organic substrate is
spongiform.
45. The method of claim 42 wherein the organic substrate is cotton
gauze or cotton flannel.
46. The method of claim 42 wherein the organic substrate is
comprised of a cellulose material.
47. The method of claim 42 wherein said oxidizing agent is nitrate
and said gaseous product is a nitrogen oxide.
48. The method of claim 42 wherein said gaseous product is
NO.sub.2.
49. The method of claim 42 wherein said initial heating step is
conducted at temperatures of up to 250.degree. C.
50. The method of claim 42 wherein at least one of said heating
steps are conducted at temperatures of up to 800.degree. C.
51. The method of claim 42 wherein at least one of said heating
steps are conducted at temperatures of up to 1400.degree. C.
52. The method of claim 42 wherein said heating steps are conducted
at temperatures below the melting temperature of the inorganic
material.
53. The method of claim 42 wherein said inorganic material is
comprised of calcium phosphate.
54. The method of claim 42 wherein said reactive blend comprises an
alcohol.
55. The method of claim 42 wherein said metal cation forms part of
said oxidizing agent.
56. The method of claim 42 wherein said oxidizing agent and metal
cation comprise a metal nitrate.
57. The method of claim 42 wherein at least one metal cation is
monovalent Li, Na, K, Rb, Cs, Cu, Ag or Hg.
58. The method of claim 42 wherein at least one metal cation is
divalent Be, Mg, Ca, Sr, Ba, Cr, Mn, Fe, Co, Ni, Cu, Zn, Rh, Pd,
Cd, Sn, Hg or Pb.
59. The method of claim 42 wherein at least one precursor cation is
tri-or tetravalent Al, Cr, Mn, Fe, Co, Ni, Ga, As, Y, Nb, Rh, In,
La, Tl, Bi, Ac, Ce, Pr, Nd, Sm, Eu, Gd, Th, Dy, Ho, Er, Tm, Yb, Lu,
U, or Pu.
60. The method of claim 42 wherein said oxidizing agent is a
nitrate.
60. The method of claim 42 wherein at least one metal cation is
calcium.
61. The method of claim 42 further comprising immersing the
inorganic shaped body in molten paraffin wax.
62. The method of claim 42 further comprising immersing the
inorganic shaped body in a gelatin solution.
63. The method of claim 42 wherein said inorganic material is
porous.
64. The method of claim 42 wherein said inorganic material is
macroporous.
65. The method of claim 42 wherein said inorganic material is
mesoporous.
66. The method of claim 42 wherein said inorganic material is
microporous.
67. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 30%.
68. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 50%.
69. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 70%.
70. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 80%.
71. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 90%.
72. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 92%.
73. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 94%.
74. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 70% together with macro-, meso-, and
microporosity.
75. The method of claim 42 wherein said inorganic material has a
pore volume of at least about 90% together with macro-, meso-, and
microporosity.
76. The method of claim 42 wherein said substrate is in a
preselected shape and the inorganic material is formed in an
approximation of that shape.
77. The method of claim 76 wherein said shape is a tube, block or
sphere.
78. The method of claim 76 wherein said shape is in the form of a
human bone, mammalian bone, or vertebra.
79. The method of claim 76 wherein said shape is hollow.
80. The method of claim 76 wherein said shape is machined.
81. Bioactive and biocompatible calcium phosphate produced by: a.
imbibing a substrate with a reactive blend comprising: at least one
phosphorus oxoacid and a calcium nitrate; b. reacting said reactive
blend while imbibed by the substrate under conditions of
temperature and pressure effective to initiate an
oxidation-reduction reaction between said oxoacid and the calcium
nitrate; c. said reaction evolving a nitrogen oxide gas and giving
rise to the calcium phosphate.
82. The calcium phosphate of claim 81 whose production further
comprises: d. subsequently heating said calcium phosphate to
temperatures of up to 800.degree. C.
83. The calcium phosphate of claim 81 whose production further
comprises: d. subsequently heating said calcium phosphate to
temperatures of up to 1400.degree. C.
84. The calcium phosphate of claim 81 characterized in that the
substrate is organic and is substantially removed in said
subsequent heating step.
85. The method of claim 81 wherein the organic substrate is
spongiform.
86. The method of claim 81 wherein the organic substrate is wool,
cotton gauze or cotton flannel.
87. The method of claim 81 wherein the organic substrate is
comprised of a cellulose material.
88. The method of claim 81 wherein the calcium phosphate is formed
in a preselected shape.
89. The method of claim 81 wherein the preselected shape is a tube,
block, or sphere.
90. The method of claim 81 wherein the preselected shape is in the
shape of a human bone, mammalian bone, or vertebra.
91. The method of claim 81 wherein the preselected shape is
machined.
92. A method for preparing an inorganic shaped body comprising: a.
mixing a paste or slurry comprising: at least one metal cation; at
least one oxidizing agent; at least one precursor anion oxidizable
by said oxidizing agent to form an oxoanion; and at least one
binding agent; b. forming said paste or slurry into a shape; c.
heating said shaped paste or slurry under conditions of temperature
and pressure effective to initiate an oxidation-reduction reaction
between said oxidizing agent and a said precursor anion; d. said
reaction evolving at least one gaseous product, giving rise to said
oxoanion and forming said inorganic shaped body.
93. The method of claim 92 wherein said inorganic shaped body is
formed by a process comprising casting, extrusion, doctor blading,
spin molding, foaming or spray forming.
94. The method of claim 92 wherein the inorganic shaped body is a
hollow extrusion.
95. The method of claim 92 wherein the inorganic shaped body is a
lattice or honeycomb.
96. An inorganic shaped body having substantially uniform macro-,
meso- and microporosity together with a pore volume of at least
about 30%.
97. The inorganic shaped body of claim 96 having a pore volume of
at least about 50%.
98. The inorganic shaped body of claim 96 having a pore volume of
at least about 70%.
99. The inorganic shaped body of claim 96 having a pore volume of
at least about 80%.
100. The inorganic shaped body of claim 96 having a pore volume of
at least about 90%.
101. The shaped body of claim 96 adapted for use as a catalyst,
catalyst support, filter, filter support, reflux surface, solid
reaction support, pyrolysis support, or encapsulant.
102. A method for restoring or repairing bone in an animal
comprising placing in the animal, at a site to be restored or
repaired, a substantially uniformly macro-, meso- and microporous
calcium phosphate shaped body having a pore volume of at least
50%.
103 The method of claim 102 wherein said pore volume is at least
about 70%
104. The method of claim 102 wherein said pore volume is at least
about 80%.
105. The method of claim 102 wherein said pore volume is at least
about 90%.
106. The method of claim 102 wherein said shaped body is in the
shape of a rod, pin, screw, cylinder, cone, truncated cone, sleeve,
concavo-convex surface or in a shape selected to mimic a portion of
said bone selected for restoration or repair.
107. The method of claim 102 wherein said shaped body is in the
shape of human bone, mammalian bone, or vertebra.
108. A method of making an inorganic powder comprising comminuting
the inorganic material of claim 1 or 42; the calcium phosphate of
claim 81, or the inorganic shaped body of claim 92.
109. The inorganic powder prepared in accordance with claim
108.
110. The inorganic powder of claim 109 having a particle size
number mean below about 10 .mu.m.
111. The inorganic powder of claim 109 having a particle size
number mean between about 0.1 and 5 .mu.m.
112. The inorganic powder of claim 109 having a particle size
number mean between about 0.5 and 2 .mu.m.
113. The inorganic powder of claim 108 adapted for use as a
component of a cosmetic or pharmaceutical or as an excipient,
additive, pigment, fluorescing agent, filler, flow control agent,
thixotropic agent, materials processing additive or radiolabel.
Description
FIELD OF THE INVENTION
[0001] This invention relates to methods for the preparation of
porous inorganic shaped bodies especially calcium
phosphate-containing shaped bodies; to the bodies thus prepared;
and to methods for use thereof In accordance with certain
embodiments of this invention, shaped bodies are provided which are
at once, highly porous and uniform in composition. They can be
produced in a wide range of geometric configurations through novel,
low temperature techniques. The shaped bodies of the invention can
be highly and uniformly porous while being self-supporting. They
can be strengthened further using a variety of techniques, thereby
forming porous composite structures. Such porous structures are
useful as cell growth scaffolds, bone grafting materials, drug
delivery vehicles, biological separation/purification media,
catalysis and other supports and in a wide range of other uses.
BACKGROUND OF THE INVENTION
[0002] There has been a continuing need for improved methods for
the preparation of mineral compositions, especially calcium
phosphate-containing minerals. This long-felt need is reflected in
part by the great amount of research found in the pertinent
literature. While such interest and need stems from a number of
industrial interests, the desire to provide materials which closely
mimic mammalian bone for use in repair and replacement of such bone
has been a major motivating force. Such minerals are principally
calcium phosphate apatites as found in teeth and bones. For
example, type-B carbonated hydroxyapatite [Ca5(PO4)3-x(CO3)x(OH) ]
is the principal mineral phase found in the body, with variations
in protein and organic content determining the ultimate
composition, crystal size, morphology, and structure of the body
portions formed therefrom.
[0003] Calcium phosphate ceramics have been fabricated and
implanted in mammals in various forms including, but not limited
to, shaped bodies and cements. Different stoichiometric
compositions such as hydroxyapatite (HAp), tricalcium phosphate
(TCP), tetracalcium phosphate (TTCP), and other calcium phosphate
salts and minerals, have all been employed to this end in an
attempt to match the adaptability, biocompatibility, structure, and
strength of natural bone. The role of pore size and porosity in
promoting revascularization, healing, and remodeling of bone is now
recognized as a critical property for bone replacement materials.
Despite tremendous efforts directed to the preparation of porous
calcium phosphate materials for such uses, significant shortcomings
still remain. This invention overcomes those shortcomings and
describes porous calcium phosphate and a wide variety of other
inorganic materials which, in the case of calcium phosphates,
closely resemble bone, and methods for the fabrication of such
materials as shaped bodies for biological, chemical, industrial,
and many other applications.
[0004] Early ceramic biomaterials exhibited problems derived from
chemical and processing shortcomings that limited stoichiometric
control, crystal morphology, surface properties, and, ultimately,
reactivity in the body. Intensive milling and comminution of
natural minerals of varying composition was required, followed by
powder blending and ceramic processing at high temperatures to
synthesize new phases for use in vivo.
[0005] A number of patents have issued which relate to ceramic
biomaterials and are incorporated herein by reference. Among these
are U.S. Pat. No. 4,880,610, B.R. Constantz , "In situ calcium
phosphate minerals method and composition;" U.S. Pat. No.
5,047,031, B. R. Constantz, "In situ calcium phosphate minerals
method;" U.S. Pat. No. 5,129,905, B. R. Constantz, "Method for in
situ prepared calcium phosphate minerals;" U.S. Pat. No. 4,149,893,
H. Aoki, et al, "Orthopaedic and dental implant ceramic composition
and process for preparing same;" U.S. Pat. No. 4,612,053, W. E.
Brown, et al, "Combinations of sparingly soluble calcium phosphates
in slurries and pastes as mineralizers and cements;" U.S. Pat. No.
4,673,355, E. T. Farris, et al, "Solid calcium phosphate
materials;" U.S. Pat. No. 4,849,193, J. W. Palmer, et al., "Process
of preparing hydroxyapatite;" U.S. Pat. No. 4,897,250, M. Sumita,
"Process for producing calcium phosphate;" U.S. Pat. No. 5,322,675,
Y. Hakamatsuka, "Method of preparing calcium phosphate;" U.S. Pat.
No. 5,338,356, M. Hirano, et al "Calcium phosphate granular cement
and method for producing same;" U.S. Pat. No. 5,427,754, F. Nagata,
et al.,"Method for production of platelike hydroxyapatite;" U.S.
Pat. No. 5,496,399, I. C. Ison, et al., "Storage stable calcium
phosphate cements;" U.S. Pat. No. 5,522,893, L. C. Chow. et al.,
"Calcium phosphate hydroxyapatite precursor and methods for making
and using same;" U.S. Pat. No. 5,545,254, L. C. Chow, et al.,
"Calcium phosphate hydroxyapatite precursor and methods for making
and using same;" U.S. Pat. No. 3,679,360, B. Rubin, et al.,
"Process for the preparation of brushite crystals;" U.S. Pat. No.
5,525,148, L.C. Chow, et al., "Self-setting calcium phosphate
cements and methods for preparing and using them;" US 5,034,352, J.
Vit, et al., "Calcium phosphate materials;" and U.S. Pat. No.
5,409,982, A. Imura, et al "Tetracalcium phosphate-based materials
and process for their preparation."
[0006] Several patents describe the preparation of porous inorganic
or ceramic structures using polymeric foams impregnated with a
slurry of preformed ceramic particles. These are incorporated
herein by reference: U.S. Pat. No. 3,833,386, L. L. Wood, et al,
"Method of preparing porous ceramic structures by firing a
polyurethane foam that is impregnated with inorganic material;"
U.S. Pat. No. 3,877,973, F. E. G. Ravault, "Treatment of permeable
materials;" U.S. Pat. No. 3,907,579, F. E. G. Ravault, "Manufacture
of porous ceramic materials;" and U.S. Pat. No. 4,004,933, F. E. G.
Ravault, "Production of porous ceramic materials." However, none of
aforementioned art specifically describes the preparation of porous
metal or calcium phosphates and none employs the methods of this
invention.
[0007] The prior art also describes the use of solution
impregnated-polymeric foams to produce porous ceramic articles and
these are incorporated herein by reference: U.S. Pat. No.
3,090,094, K. Schwartzwalder, et al, "Method of making porous
ceramic articles;" US 4,328,034 C. N. Ferguson, "Foam Composition
and Process;" U.S. Pat. No. 4,859,383, M. E. Dillon, "Process of
Producing a Composite Macrostructure of Organic and Inorganic
Materials;" U.S. Pat. No. 4,983,573, J.D. Bolt, et al, "Process for
making 90.degree. K. superconductors by impregnating cellulosic
article with precursor solution;" U.S. Pat. No. 5,219,829, G.
Bauer, et al, "Process and apparatus for the preparation of
pulverulent metal oxides for ceramic compositions;" GB 2,260,538,
P. Gant, "Porous ceramics;" U.S. Pat. No. 5,296,261, J. Bouet, et
al, "Method of manufacturing a sponge-type support for an electrode
in an electrochemical cell;" US 5,338,334, Y. S. Zhen, et al,
"Process for preparing submicron/nanosize ceramic powders from
precursors incorporated within a polymeric foam;" and S. J. Powell
and J. R. G. Evans, "The structure of ceramic foams prepared from
polyurethane-ceramic suspensions," Materials & Manufacturing
Processes, 10(4):757 (1995). The focus of this art is directed to
the preparation of either metal or metal oxide foams and/or
particles. None of the disclosures of these aforementioned
references mentions in situ solid phase formation via redox
precipitation reaction from homogeneous solution as a formative
method.
[0008] The prior art also discloses certain methods for
fabricating, inorganic shaped bodies using natural, organic
objects. These fabrication methods, however, are not without
drawbacks which include cracking upon drying the green body and/or
upon firing. To alleviate these problems, the fabrication processes
typically involve controlled temperature and pressure conditions to
achieve the desired end product. In addition, prior fabrication
methods may include the additional steps of extensive material
preparation to achieve proper purity, particle size distribution
and orientation, intermediate drying and radiation steps, and
sintering at temperatures above the range desired for employment in
the present invention. For example, U.S. Pat. No. 5,298,205 issued
to Hayes et. al. entitled "Ceramic Filter Process", incorporated
herein by reference, discloses a method of fabricating a porous
ceramic body from an organic sponge saturated in an aqueous slurry
comprised of gluten and particulate ceramic material fired at a
temperature range from 1,100.degree. to 1,300.degree. C. Hayes
teaches that the saturated sponge must be dehydrated prior to
firing via microwave radiation, and includes a pre-soak heating
step, and a hot pressing step.
[0009] While improvements have been made in materials synthesis and
ceramic processing technology leading to porous ceramics and
ceramic biomaterials, improved preparative methods, and the final
products these methods yield, are still greatly desired. Generation
of controlled porosity in ceramic biomaterials generally, and in
calcium phosphate materials in particular, is crucial to the
effective in vitro and in vivo use of these synthetic materials for
regenerating human cells and tissues. This invention provides both
novel, porous calcium phosphate materials and methods for preparing
them. Methods relating to calcium phosphate-containing
biomaterials, which exhibit improved biological properties, are
also greatly desired despite the great efforts of others to achieve
such improvements.
[0010] Accordingly, it is a principal object of this invention to
provide improved inorganic, porous, shaped bodies, especially those
formed of calcium phosphate.
[0011] A further object of the invention is to provide methods for
forming such materials with improved yields, lower processing
temperatures, greater compositional flexibility, and better control
of porosity.
[0012] Yet another object provides materials with micro-, meso-,
and macroporosity, as well as the ability to generate shaped porous
solids having improved uniformity, biological activity, catalytic
activity, and other properties.
[0013] Another object is to provide porous materials which are
useful in the repair and/or replacement of bone in orthopaedic and
dental procedures.
[0014] An additional object is to prepare a multiplicity of high
purity, complex shaped objects, formed at temperatures below those
commonly used in traditional firing methods.
[0015] Further objects will become apparent from a review of the
present specification.
SUMMARY OF THE INVENTION
[0016] The present invention is directed to new inorganic bodies,
especially controllably porous bodies, which can be formed into
virtually any geometric shape. The novel preparative methods of the
invention utilize redox precipitation chemistry or aqueous solution
chemistry, which is described in pending U.S. patent application
Ser. No. 08/784,439 assigned to the present assignee and,
incorporated herein by reference. In accordance with certain
preferred embodiments, the redox precipitation chemistry is
utilized in conjunction with a sacrificial, porous cellular
support, such as an organic foam or sponge, to produce a porous
inorganic product which faithfully replicates both the bulk
geometric form as well as the macro-, meso-, and microstructure of
the precursor organic support. The aqueous solution, because of its
unique chemistry, has a high solids equivalent, yet can essentially
be imbibed fully into and infiltrate thoroughly the microstructure
of the sacrificial organic precursor material. This extent of
infiltration allows the structural details and intricacies of the
precursor organic foam materials to be reproduced to a degree
heretofore unattainable. This great improvement can result in
porous, inorganic materials having novel microstructural features
and sufficient robustness to be handled as coherent bodies of
highly porous solid.
[0017] The invention also gives rise to porous inorganic materials
having improved compositional homogeneity, multiphasic character,
and/or modified crystal structures at temperatures far lower than
those required in conventional formation methods. In addition, the
invention also gives rise to porous inorganic composites comprising
mineral scaffolds strengthened and/or reinforced with polymers,
especially film-forming polymers, such as gelatin.
[0018] The new paradigm created by this invention is facilitated by
a definition of terms used in the description of embodiments. The
general method starts with infiltrant solutions produced from raw
materials described herein as salts, aqueous solutions of salts,
stable hydrosols or other stable dispersions, and/or inorganic
acids. The sacrificial, porous organic templates used in some
embodiments may be organic foams, cellular solids and the like,
especially open-cell hydrophilic material which can imbibe the
aqueous infiltrant solutions. Both the precursor organic templates,
as well as the inorganic replicas produced in accordance within
this invention, display a porosity range of at least 3 orders of
magnitude. This range of porosity can be described as macro-, meso-
and microporous. Within the scope of this invention, macroporosity
is defined as having a pore diameter greater than or equal to 100
microns, mesoporosity is defined as having a pore diameter less
than 100 microns but greater than or equal to 10 microns, and
microporosity is defined as having a pore diameter less than 10
microns.
[0019] In addition to the controlled macro-, meso- and
microporosity ranges, inorganic shaped bodies have been fabricated
possessing pore volumes of at least about 30%. In preferred
embodiments, pore volumes of over 50% have been attained and pore
volumes in excess of 70% or 80% are more preferred. Materials
having macro-, meso- and microporosity together with pore volumes
of at least about 90% can be made as can those having pore volumes
over 92% and even 94%. In some cases, pore volumes approaching 95%
have been ascertained in products which, nevertheless, retain their
structural integrity and pore structure.
[0020] The phases produced by the methods of this invention [Redox
Precipitation Reaction (RPR) and HYdrothermal PRocessing (HYPR)]
initially are intermediate or precursor minerals, which can be
easily converted to a myriad of pure and multiphasic minerals of
previously known and, in some cases, heretofore undefined
stoichiometry, generally via a thermal treatment under modest
firing regimens compared to known and practiced conventional
art.
[0021] In accordance with certain embodiments of the present
invention, methods are provided for the restoration of bony tissue.
In this regard, an area of bony tissue requiring repair as a result
of disease, injury, desired reconfiguration and the like, is
identified and preferably measured. A block of porous calcium
phosphate material can be made to fit the dimensions of the missing
or damaged bony tissue and implanted in place by itself or in
conjunction with biocompatible bonding material compositions such
as those disclosed in U.S. Pat. No. 5,681,872 issued in the name of
E. M. Erbe on Oct. 28, 1997 and incorporated herein by reference.
The calcium phosphate material can also be used as a "sleeve" or
form for other implants, as a containment vessel for the bone
grafting material which is introduced into the sleeve for the
repair, and in many other contexts.
[0022] A major advantage of the restoration is that after
polymerization, it has a significant, inherent strength, such that
restoration of load-bearing bony sites can be achieved. While
immobilization of the effected part will likely still be required,
the present invention permits the restoration of many additional
bony areas than has been achievable heretofore. Further, since the
porous calcium phosphate scaffolding material of the present
invention is biocompatible and, indeed, bioactive, osteogenesis can
occur. This leads to bone infiltration and replacement of the
calcium phosphate matrix with autologous bone tissue.
[0023] The calcium phosphate scaffolding material of the present
invention may also be made into -shaped bodies for a variety of
uses. Thus, orthopaedic appliances such as joints, rods, pins, or
screws for orthopaedic surgery, plates, sheets, and a number of
other shapes may be formed from the material in and of itself or
used in conjunction with conventional appliances that are known in
the art. Such hardened compositions can be bioactive and can be
used, preferably in conjunction with hardenable compositions in
accordance with the present invention in the form of gels, pastes,
or fluids, in surgical techniques. Thus, a screw or pin can be
inserted into a broken bone in the same way that metal screws and
pins are currently inserted, using conventional bone cements or
restoratives in accordance with the present invention or otherwise.
The bioactivity of the present hardenable materials give rise to
osteogenesis, with beneficial medical or surgical results.
[0024] The methods of the invention are energy efficient, being
performed at relatively low temperature; have high yields; and are
amenable to careful control of product shape, macro- and
microstructure, porosity, and chemical purity. Employment as
bioactive ceramics is a principal, anticipated use for the
materials of the invention, with improved properties being extant.
Other uses of the porous minerals and processes for making the same
are also within the spirit of the invention.
[0025] The present invention also provides exceptionally fine,
uniform powders of inorganic materials. Such powders have uniform
morphology, uniform composition and narrow size distribution. They
may be attained through the comminution of shaped bodies in
accordance with the invention and have wide utility in chemistry,
industry, medicine and otherwise.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 depicts an aggregated physical structure of an RPR
generated, multiphasic .beta.-tricalcium phosphate (P-TCP) +type-B
carbonated apatite (c-HAp)
[.beta.-Ca3(PO4)2+Ca5(PO.sub.4)3-x(CO3)x(OH)] prepared in
accordance with one embodiment of this invention. The entire
agglomerated particle is approximately 10 .mu.m, and the individual
crystallites are typically less than about 1 .mu.m and relatively
uniform in particle size and shape.
[0027] FIG. 2 represents assembled monetite, CaHPO.sub.4 particles
formed from a hydrothermal precipitation in accordance with certain
methods taught by this invention. The entire particle assemblage is
typically about 30 .mu.m and is comprised of relatively uniformly
rectangular cubes and plate-like crystallites of various sizes and
aspect ratios.
[0028] FIG. 3 illustrates a water purification disk that is
comprised of the porous inorganic material of the present invention
and is contained within an exterior housing for filtration or
separation purposes.
[0029] FIG. 4 illustrates shaped bodies of porous inorganic
material of the present invention used as a catalyst support within
a hot gas reactor or diffusor.
[0030] FIG. 5 illustrates shaped bodies of porous calcium phosphate
material of the present invention implanted at several sites within
a human femur for cell seeding, drug delivery, protein adsorption,
or growth factor scaffolding purposes.
[0031] FIGS. 6A and FIG. 6B illustrate one embodiment of porous
calcium phosphate scaffolding material of the present invention
used as an accommodating sleeve in which a tooth is screwed,
bonded, cemented, pinned, anchored, or otherwise attached in
place.
[0032] FIGS. 7 and 7A illustrate another embodiment of the porous
calcium phosphate scaffolding material of the present invention
used as a cranio-maxillofacial, zygomatic reconstruction and
mandibular implant.
[0033] FIGS. 8A and 8B illustrate one embodiment of the porous
calcium phosphate scaffolding material of the present invention
shaped into a block form and used as a tibial plateau
reconstruction that is screwed, bonded, cemented, pinned, anchored,
or otherwise attached in place.
[0034] FIG. 9 illustrates an embodiment of the porous calcium
phosphate scaffolding material of the present invention shaped into
a block or sleeve form and used for the repair or replacement of
bulk defects in metaphyseal bone, oncology defects or screw
augmentation.
[0035] FIGS. 10A and 10B illustrate an embodiment of the porous
calcium phosphate scaffolding material of the present invention
shaped into a sleeve form and used for impaction grafting to
accommodate an artificial implant said sleeve form being screwed,
bonded, pinned or otherwise attached in place.
[0036] FIG. 11 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous calcium phosphate material fired at 500.degree. C.
in accordance with one embodiment of this invention. The sample
consists of a biphasic mixture of whitlockite
Ca.sub.3(PO.sub.4).sub.2 (PDF 09-0169) and hydroxyapatite
Ca.sub.5(PO.sub.4).sub.3(OH) (PDF 09-0432).
[0037] FIG. 12 is a 50.times. magnification scanning electron
micrograph of a virgin cellulose sponge material used to prepare
several of the embodiments of this invention.
[0038] FIG. 13 is a 100.times. magnification scanning electron
micrograph of porous calcium phosphate material fired at
500.degree. C. in accordance with one embodiment of this
invention.
[0039] FIG. 14 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous calcium phosphate material fired at 1100.degree.
C. in accordance with one embodiment of this invention. The sample
consists of whitlockite Ca.sub.3(PO.sub.4).sub.2 (PDF 09-0169).
[0040] FIG. 15 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous calcium phosphate material fired at 1350.degree.
C. in accordance with one embodiment of this invention. The sample
consists of whitlockite Ca.sub.3(PO.sub.4).sub.2 (PDF 09-0169).
[0041] FIG. 16 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous calcium phosphate material fired at 800.degree. C.
in accordance with one embodiment of this invention. The sample
consists of calcium pyrophosphate, Ca.sub.2P.sub.2O.sub.7 (PDF
33-0297).
[0042] FIG. 17 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous zinc phosphate material fired at 500.degree. C. in
accordance with one embodiment of this invention. The sample
consists of zinc phosphate, Zn.sub.3(PO.sub.4).sub.2 (PDF
30-1490).
[0043] FIG. 18 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous neodymium phosphate material fired at 500.degree.
C. in accordance with one embodiment of this invention. The sample
consists of neodymium phosphate, NdPO.sub.4 (PDF 25-1065).
[0044] FIG. 19 is an X-ray diffraction (XRD) plot of a pulverized
sample of porous aluminum phosphate material fired at 500.degree.
C. in accordance with one embodiment of this invention. The sample
consists of aluminum phosphate, AlPO.sub.4 (PDF 11-0500).
[0045] FIG. 20 is a 23.times. magnification scanning electron
micrograph depicting the macro- and meso-porosity of porous calcium
phosphate material fired at 500.degree. C. and reinforced with
gelatin in accordance with one embodiment of this invention.
[0046] FIG. 21 is a 25.times. magnification scanning electron
micrograph of sheep trabecular bone for comparative purposes.
[0047] FIG. 22 is a 2000.times. magnification scanning electron
micrograph of the air-dried gelatin treated inorganic sponge
depicted in FIG. 20 which exhibits meso- and microporosity in the
calcium phosphate matrix. FIGS. 20 and 22, together, demonstrate
the presence of macro-, meso-, and microporosity simultaneously in
a highly porous product.
[0048] FIG. 23 is an X-ray diffraction (XRD) plot of a pulverized
sample of the ash remaining after firing at 500.degree. C. of the
virgin cellulose sponge starting material used to prepare several
of the embodiments of this invention. The ash sample consists of a
biphasic mixture of magnesium oxide, MgO (major) (PDF 45-0946) and
sodium chloride, NaCl (minor) (PDF 05-0628).
[0049] FIG. 24 is a 20.times. magnification scanning electron
micrograph of a virgin cellulose sponge starting material, expanded
from its compressed state, used to prepare several of the
embodiments of this invention.
[0050] FIG. 25 is a 20.times. magnification scanning electron
micrograph of porous calcium phosphate material fired at
800.degree. C. and reinforced with gelatin in accordance with one
embodiment of this invention.
[0051] FIG. 26 depicts a calcium phosphate porous body, produced in
accordance with one embodiment of this invention partially wicked
with blood.
[0052] FIG. 27 shows a cylinder of calcium phosphate prepared in
accordance with one embodiment of this invention, implanted into
the metaphyseal bone of a canine.
[0053] FIG. 28 is an X-ray diffraction plot of a pulverized sample
of a cation substituted hydroxyapatite material processed in
accordance with the methods described in this invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0054] In accordance with the present invention, methods are
provided for preparing shapes comprising an intermediate precursor
mineral of at least one metal cation and at least one oxoanion.
These methods comprise preparing an aqueous solution of the metal
cation and at least one oxidizing agent. The solution is augmented
with at least one soluble precursor anion oxidizable by said
oxidizing agent to give rise to the precipitant oxoanion. The
oxidation-reduction reaction thus contemplated is conveniently
initiated by heating the solution under conditions of temperature
and pressure effective to give rise to said reaction. In accordance
with preferred embodiments of the invention, the
oxidation-reduction reaction causes at least one gaseous product to
evolve and the desired intermediate precursor mineral to
precipitate from the solution.
[0055] The intermediate precursor mineral thus prepared can either
be used "as is" or can be treated in a number of ways. Thus, it may
be heat treated in accordance with one or more paradigms to give
rise to a preselected crystal structure or other preselected
morphological structures therein. In accordance with preferred
embodiments, the oxidizing agent is nitrate ion and the gaseous
product is a nitrogen oxide, generically depicted as NO.sub.x(g).
It is preferred that the precursor mineral provided by the present
methods be substantially homogeneous. It is also preferred for many
embodiments that the temperature reached by the oxidation-reduction
reaction not exceed about 150.degree. C. unless the reaction is run
under hydrothermal conditions or in a pressure vessel.
[0056] In accordance with other preferred embodiments, the
intermediate precursor mineral provided by the present invention is
a calcium phosphate. It is preferred that such mineral precursor
comprise, in major proportion, a solid phase which cannot be
identified singularly with any conventional crystalline form of
calcium phosphate. At the same time, the calcium phosphate mineral
precursors of the present invention are substantially homogeneous
and do not comprise a physical admixture of naturally occurring or
conventional crystal phases.
[0057] In accordance with preferred embodiments, the low
temperature processes of the invention lead to the homogeneous
precipitation of high purity powders from highly concentrated
solutions. Subsequent modest heat treatments convert the
intermediate material to e.g. novel monophasic calcium phosphate
minerals or novel biphasic -tricalcium phosphate (.beta.-TCP)
+type-B, carbonated apatite (c-HAp) [.beta.-Ca.sub.3(PO.sub.-
4).sub.2+Ca.sub.5(PO.sub.4).sub.3-x(CO.sub.3).sub.x(OH)]
particulates.
[0058] In other preferred embodiments, calcium phosphate salts are
provided through methods where at least one of the precursor anions
is a phosphorus oxoanion, preferably introduced as hypophosphorous
acid or a soluble alkali or alkaline-earth hypophosphite salt. For
the preparation of such calcium phosphates, it is preferred that
the initial pH be maintained below about 3, and still more
preferably below about 1.
[0059] The intermediate precursor minerals prepared in accordance
with the present methods are, themselves, novel and not to be
expected from prior methodologies. Thus, such precursor minerals
can be, at once, non-stoichiometric and possessed of uniform
morphology.
[0060] It is preferred in connection with some embodiments of the
present invention that the intermediate precursor minerals produced
in accordance with the present methods be heated, or otherwise
treated, to change their properties. Thus, such materials may be
heated to temperatures as low as 300.degree. C. up to about
800.degree. C. to give rise to certain beneficial transformations.
Such heating will remove extraneous materials from the mineral
precursor, will alter its composition and morphology in some cases,
and can confer upon the mineral a particular and preselected
crystalline structure. Such heat treatment can be to temperatures
which are considerably less than those used conventionally in
accordance with prior methodologies to produce end product mineral
phases. Accordingly, the heat treatments of the present invention
do not, necessarily, give rise to the "common" crystalline
morphologies of monetite, dicalcium or tricalcium phosphate,
tetracalcium phosphate, etc., but, rather, they can lead to new and
unobvious morphologies which have great utility in the practice of
the present invention.
[0061] The present invention is directed to the preparation,
production and use of shaped bodies of inorganic materials. It will
be appreciated that shaped bodies can be elaborated in a number of
ways, which shaped bodies comprise an inorganic material. A
preferred method for giving rise to the shaped bodies comprising
minerals is through the use of subject matter disclosed in U.S.
Ser. No. 08/784,439 filed Jan. 16, 1997, assigned to the assignee
of the present invention and incorporated herein by reference. In
accordance with techniques preferred for use in conjunction with
the present invention, a blend of materials are formed which can
react to give rise to the desired mineral, or precursor thereof, at
relatively low temperatures and under relatively flexible reaction
conditions. Preferably, the reactive blends thus used include
oxidizing agents and materials which can be oxidized by the
oxidizing agent, especially those which can give rise to a
phosphorus oxoanion. Many aspects of this chemistry are described
hereinafter in the present specification. It is to be understood,
however, that such reactive blends react at modest temperatures
under modest reaction conditions, usually through the evolution of
a nitrogen oxide gas, to give rise to the minerals desired for
preparation or to materials which may be transformed such as
through heating or sintering to form such minerals. A principal
object of the present invention is to permit such minerals to be
formed in the form of shaped bodies.
[0062] It will be appreciated that preferred compositions of this
invention exhibit high degrees of porosity. It is also preferred
that the porosity occur in a wide range of effective pore sizes. In
this regard, persons skilled in the art will appreciate that
preferred embodiments of the invention have, at once,
macroporosity, mesoporosity and microporosity. Macroporosity is
characterized by pore diameters greater than about 100 .mu.m.
Mesoporosity is characterized by pore diameters between about 100
and 10 .mu.m, while microporosity occurs when pores have diameters
below about 10 .mu.m. It is preferred that macro-, meso- and
microporosity occur simultaneously in products of the invention. It
is not necessary to quantify each type of porosity to a high
degree. Rather, persons skilled in the art can easily determine
whether a material has each type of porosity through examination,
such as through the preferred method of scanning electron
microscopy. While it is certainly true that more than one or a few
pores within the requisite size range are needed in order to
characterize a sample as having a substantial degree of that
particular form of porosity, no specific number or percentage is
called for. Rather, a qualitative evaluation by persons skilled in
the art shall be used to determine macro-, meso- and
microporosity.
[0063] It is preferred that the overall porosity of materials
prepared in accordance with this invention be high. This
characteristic is measured by pore volume, expressed as a
percentage. Zero percent pore volume refers to a fully dense
material, which, perforce, has no pores at all. One hundred percent
pore volume cannot meaningfully exist since the same would refer to
"all pores" or air. Persons skilled in the art understand the
concept of pore volume, however and can easily calculate and apply
it. For example, pore volume may be determined in accordance with
W. D. Kingery, Introduction to Ceramics, 1960 p. 416 (Wiley, 1060),
who provides a formula for determination of porosity. Expressing
porosity as a percentage yields pore volume. The formula is: Pore
Volume (1-f.sub.p) 100%, where f.sub.p is fraction of theoretical
density achieved.
[0064] Pore volumes in excess of about 30% are easily achieved in
accordance with this invention while materials having pore volumes
in excess of 50 or 60% are also routinely attainable. It is
preferred that materials of the invention have pore volumes of at
least about 75%. More preferred are materials having pore volumes
in excess of about 85%, with 90% being still more preferred. Pore
volumes greater than about 92% are possible as are volumes greater
than about 94%. In some cases, materials with pore volumes
approaching 95% can be made in accordance with the invention. In
preferred cases, such high pore volumes are attained while also
attaining the presence of macro- meso- and microporosity as well as
physical stability of the materials produced. It is believed to be
a great advantage to be able to prepare inorganic shaped bodies
having macro-, meso- and microporosity simultaneously with high
pore volumes as described above.
[0065] It has now been found that such shaped bodies may be formed
from minerals in this way which have remarkable macro- and
microstructures. In particular, a wide variety of different shapes
can be formed and bodies can be prepared which are machinable,
deformable, or otherwise modifiable into still other, desired
states. The shaped bodies have sufficient inherent physical
strength allowing that such manipulation can be employed. The
shaped bodies can also be modified in a number of ways to increase
or decrease their physical strength and other properties so as to
lend those bodies to still further modes of employment. Overall,
the present invention is extraordinarily broad in that shaped
mineral bodies may be formed easily, inexpensively, under carefully
controllable conditions, and with enormous flexibility. Moreover,
the microstructure of the materials that can be formed from the
present invention can be controlled as well, such that they may be
caused to emulate natural bone, to adopt a uniform microstructure,
to be relatively dense, relatively porous, or, in short, to adopt a
wide variety of different forms. The ability to control in a
predictable and reproducible fashion the macrostructure,
microstructure, and mineral identity of shaped bodies in accordance
with the present invention under relatively benign conditions using
inexpensive starting materials lends the technologies of the
present invention to great medical, chemical, industrial,
laboratory, and other uses.
[0066] In accordance with certain preferred embodiments of the
present invention, a reactive blend in accordance with the
invention is caused to be imbibed into a material which is capable
of absorbing it. It is preferred that the material have significant
porosity, be capable of absorbing significant amounts of the
reactive blend via capillary action, and that the same be
substantially inert to reaction with the blend prior to its
autologous oxidation-reduction reaction. It has been found to be
convenient to employ sponge materials, especially cellulose sponges
of a kind commonly found in household use for this purpose. Other
sponges, including those which are available in compressed form
such as Normandy sponges, are also preferred in certain
embodiments. The substrate used to imbibe the reactive blend,
however, are not limited to organic materials and can include
inorganic materials such as fiberglass.
[0067] The sponges are caused to imbibe the reactive blend in
accordance with the invention and are subsequently, preferably
blotted to remove excess liquid. The reactive blend-laden sponge is
then heated to whatever degree may be necessary to initiate the
oxidation-reduction reaction of the reactive blend. Provision is
generally made for the removal of by-product noxious gases, chiefly
nitrogen oxide gases, from the site of the reaction. The reaction
is exothermic, however the entire reacted body does not generally
exceed a few hundred degrees centigrade. In any event, the reaction
goes to completion, whereupon what is seen is an object in the
shape of the original sponge which is now intimately comprised of
the product of the oxidation reduction reaction. This material may
either be the finished, desired mineral, or may be a precursor from
which the desired product may be obtained by subsequent
PRocessing.
[0068] Following the initial oxidation-reduction reaction, it is
convenient and, in many cases, preferred to heat treat the reacted
product so as to eliminate the original sponge. In this way, the
cellulosic component of the sponge is pyrolyzed in a fugitive
fashion, leaving behind only the mineral and in some cases, a small
amount of ash. The resulting shaped body is in the form of the
original sponge and is self-supporting. As such, it may be used
without further transformation or it may be treated in one or more
ways to change its chemical and or physical properties. Thus, the
shaped body following the oxidation-reduction reaction, can be heat
treated at temperatures of from about 250.degree. C. to about
1400.degree. C., preferably from 500.degree. C. to about
1000.degree. C., and still more preferably from about 500.degree.
C. to about 800.degree. C. Thus, a precursor mineral formed from
the oxidation-reduction reaction may be transformed into the final
mineral desired for ultimate use. A number of such transformations
are described in the examples to the present application and still
others will readily occur to persons skilled in the art.
[0069] It will be appreciated that temperatures in excess of
250.degree. C. may be employed in initiating the
oxidation-reduction reaction and, indeed, any convenient
temperature may be so utilized. Moreover, methods of initiating the
reaction where the effective temperature is difficult or impossible
to determine, such a microwave heating, may also be employed. The
preferred procedures, however, are to employ reaction conditions to
initiate, and propagate if necessary, the reaction are below the
temperature wherein melting of the products occur. This is in
distinction with conventional glass and ceramic processing
methods.
[0070] The shaped bodies thus formed may be used in a number of
ways directly or may be further modified. Thus, either the
as-formed product of the oxidation-reduction reaction may be
modified, or a resulting, transformed mineral structure may be
modified, or both. Various natural and synthetic polymers,
pre-polymers, organic materials, metals and other adjuvants may be
added to the inorganic structures thus formed. Thus, wax, glycerin,
gelatin, pre-polymeric materials such as precursors to various
nylons, acrylics, epoxies, polyalkylenes, and the like, may be
caused to permeate all or part of the shaped bodies formed in
accordance with the present invention. These may be used to modify
the physical and chemical nature of such bodies. In the case of
polymers, strength modifications may easily be obtained.
Additionally, such materials may also change the chemical nature of
the minerals, such as by improving their conductivity, resistance
to degradation, electrolytic properties, electrochemical
properties, catalytic properties, or otherwise. All such
modifications are contemplated by the present invention.
[0071] As will be appreciated, the shaped bodies prepared in
accordance with the present invention may be formed in a very large
variety of shapes and structures. It is very easy to form cellulose
sponge material into differing shapes such as rings, rods,
screw-like structures, and the like. These shapes, when caused to
imbibe a reactive blend, will give rise to products which emulate
the original shapes. It is also convenient to prepare blocks,
disks, cones, frustrurns or other gross shapes in accordance with
the present invention which shapes can be machined, cut, or
otherwise manipulated into a final desired configuration. Once this
has been done, the resulting products may be used as is or may be
modified through the addition of gelatin, wax, polymers, and the
like, and used in a host of applications.
[0072] When an inherently porous body such as a sponge is used as a
substrate for the imbibition of reactive blend and the subsequent
elaboration of oxidation-reduction product, the resulting product
replicates the shape and morphology of the sponge. Modifications in
the shape of the sponge, and in its microstructure can give rise to
modifications in at least the intermediate structure and gross
structures of the resulting products. It has been found, however,
that the microstructure of shaped bodies prepared in accordance
with the present invention frequently include complex and highly
desirable features. Thus, on a highly magnified scale,
microstructure of materials produced in accordance with the present
invention can show significant microporosity. In several
embodiments of the present invention, the microstructure can be
custom-tailored based upon the absorbent material selected as the
fugitive support. One particular embodiment, which used a kitchen
sponge as the absorbent material, exhibited a macro- and
microstructure similar to the appearance of ovine trabecular bone.
This highly surprising, yet highly desirable result gives rise to
obvious benefits in terms of the replication of bony structures and
to the use of the present invention in conjunction with the
restoration of bony tissues in animals and especially in
humans.
[0073] Other macro- and microstructures may be attained through the
present invention, however. Thus, through use of the embodiments of
the present invention, great diversity may be attained in the
preparation of mineral structures not only on a macroscopic but
also on a microscopic level. Accordingly, the present invention
finds utility in a wide variety of applications. Thus, the shaped
bodies may be used in medicine, for example for the restoration of
bony defects and the like. The materials may also be used for the
delivery of medicaments internal to the body. In this way, the
porosity of a material formed in accordance with the invention may
be all or partially filled with another material which either
comprises or carries a medicament such as a growth hormone,
antibiotic, cell signaling material, or the like. Indeed, the
larger porous spaces within some of the products of the present
invention may be used for the culturing of cells within the human
body. In this regard, the larger spaces are amenable to the growth
of cells and can be permeated readily by bodily fluids such as
certain blood components. In this way, growing cells may be
implanted in an animal through the aegis of implants in accordance
with the present invention. These implants may give rise to
important biochemical or therapeutic or other uses.
[0074] The invention finds great utility in chemistry as well.
Shaped bodies formed from the present invention may be formed to
resemble saddles, rings, disks, honeycombs, spheres, tubes,
matrixes, and, in short, a huge array of shapes, which shapes may
be used for engineering purposes. Thus, such shapes may be made
from minerals which incorporate catalytic components such as rare
earths, precious and base metals, palladium, platinum, Raney nickel
and the like for catalytic use. These shapes may also be used for
column packing for distillation and other purposes. Indeed, the
shapes may be capable of serving a plurality of uses at once, such
as being a substrate for refluxing while acting as a catalyst at
the same time.
[0075] The bodies of the present invention will also be suitable
for chromatography and other separation and purification
techniques. Thus, they may serve as substrates for mobile phases in
the same way that a capillary suspends a gelatinous material for
capillary gel electrophoresis.
[0076] The present invention also provides filtration media. As is
apparent, the porous structures of the present invention may serve
as filters. Due to the ability to formulate these shaped bodies in
a wide variety of carefully controlled ways, some unique structures
may be attained. Thus, an anisotropic membrane, as known to persons
of ordinary skill in the art, and frequently referred to as a
"Michaels" membrane may be used for the imbibation of reactive
blend in accordance with the invention. Following redox reaction
and removal of the membranous material as a fugitive phase, the
resulting inorganic structure is also anisotropic. It is thus
possible to utilize materials and shaped bodies in accordance with
the present invention as an anisotropic but inorganic filtration
media. Since it is also possible to include a number of inorganic
materials therein, such filters may be caused to be inherently
bacteriostatic and non-fouling. It has been shown, heretofore, that
anisotropic membranes such as polysulfone and other membranes are
capable of nurturing and growing cells for the purposes of
delivering cellular products into a reaction screen. It is now
possible to accomplish the same goals using wholly inorganic
structures prepared in accordance with this invention.
[0077] In addition to the foregoing, it is possible to prepare and
modify shaped bodies in accordance with the present invention in a
variety of other ways. Thus, the shaped bodies may be coated, such
as with a polymer. Such polymers may be any of the film forming
polymers or otherwise and may be used for purposes of activation,
conductivity, passivation, protection, or other chemical and
physical modification. The bodies may also be contacted with a
"keying agent" such as a silane, or otherwise to enable the
grafting of different materials onto the surface of the
polymer.
[0078] The shaped bodies of the invention may also be used for the
growth of oligomers on their surfaces. This can be done in a manner
analogous to a Merrifield synthesis, an oligonucleotide synthesis
or otherwise. Such shaped bodies may find use in conjunction with
automated syntheses of such oligomers and may be used to deliver
such oligomers to the body of an animal, to an assay, to a
synthetic reaction vessel, or otherwise. Since the mineral
composition of the shaped bodies of this invention may be varied so
widely, it is quite suitable to the elaboration of oligomers as
suggested here and above. Grafting of other inorganic materials,
silanes, especially silicones and similar materials, is a
particular feature of the present invention. The grafting
reactions, keying reactions, oligomer extension reactions and the
like are all known to persons skilled in the art and will not be
repeated here. Suffice it to say that all such reactions are
included within the scope of the present invention.
[0079] The shaped bodies of the invention may also be coated
through surface layer deposition techniques such as plasma coating,
electroless plating, chemical vapor deposition (CVD), physical
vapor deposition (PVD), or other methods. In such a way, the
surface structure of the shaped bodies may be modified in carefully
controlled ways for catalytic, electronic, and other purposes. The
chemistry and physics of chemical vapor deposition and other
coating techniques are known to persons of ordinary skill in the
art whose knowledge is hereby assumed.
[0080] In accordance with other embodiments of the invention, the
shaped bodies produced hereby may be comminuted to yield highly
useful and unique powder materials finding wide utility. Thus,
shaped bodies may be crushed, milled, etc. and preferably
classified or measured, such as with a light scattering instrument,
to give rise to fine powders. Such powders are very small and
highly uniform, both in size, shape and chemical composition.
Particles may be prepared having particle size number means less
than about 0.1 .mu.m or 100 nanometers. Smaller mean sized may also
be attained. Thus, this invention provides highly uniform inorganic
materials in powder form having particle sizes, measured by light
scattering techniques such that the number mean size is between
about 0.1 and 5.0 .mu.m. Particle sizes between about 0.5 and 2.0
.mu.m may also be attained. It may, in some embodiments, be desired
to classify the powders in order to improve uniformity of size.
[0081] The morphology of the particles is highly uniform, deriving,
it is thought, from the microporosity of the shaped bodies from
which they arise. The particles are also highly uniform chemically.
Since they arise from a chemical reaction from a fully homogenous
solution, such uniformity is much greater than is usually found in
glass or ceramic melts.
[0082] Particle size number means are easily determined with a
Horiba LA-910 instrument. Number means refers to the average or
mean number of particles having the size or size range in
question.
[0083] Such powders are very useful, finding use in cosmetics,
pharmaceuticals, excipients, additives, pigments, fluorescing
agents, fillers, flow control agents, thixotropic agents, materials
processing, radiolabels, and in may other fields of endeavor. For
example, a molded golf ball may easily be made such as via the
processes of Bartsch, including a calcium phosphate powder of this
invention admixed with a crosslinked acrylic polymer system.
[0084] In conjunction with certain embodiments of the present
invention, shaping techniques are employed on the formed, shaped
bodies of the present invention. Thus, such bodies may be machined,
pressed, stamped, drilled, lathed, or otherwise mechanically
treated to adopt a particular shape both externally and internally.
As will be appreciated, the internal microstructure of the bodies
of the present invention can be altered thru the application of
external force where such modifications are desired. Thus, preforms
may be formed in accordance with the invention from which shapes
may be cut or formed. For example, an orthopaedic sleeve for a bone
screw may be machined from a block of calcium phosphate made
hereby, and the same tapped for screw threads or the like.
Carefully controllable sculpting is also possible such that
precisely-machined shapes may be made for bioimplantation and other
uses.
[0085] While many of the present embodiments rely upon the
imbibation of reactive blends by porous, organic media such as
sponges and the like, it should be appreciated that many other ways
of creating shaped bodies in accordance with this invention also
exist. In some of these embodiments, addition of materials, either
organic or inorganic, which serve to modify the characteristic of
the reactive blend may be beneficial. As an example of this, flow
control agents may be employed. Thus, it may be desirable to admix
a reactive blend in accordance with the invention together with a
material such as a carboxymethyl or other cellulose or another
binding agent to give rise to a paste or slurry. This paste or
slurry may then be formed and the oxidation reduction reaction
initiated to give rise to particular shapes. For example, shaped
bodies may be formed through casting, extrusion, foaming, doctor
blading, spin molding, spray forming, and a host of other
techniques. It is possible to extrude hollow shapes in the way that
certain forms of hollow pasta are extruded. Indeed, machinery
useful for the preparation of certain food stuffs may also find
beneficial use in conjunction with certain embodiments of the
present invention. To this end, food extrusion materials such as
that used for the extrusion of "cheese puffs" or puffed cereals may
be used. These combine controllable temperature and pressure
conditions with an extrusion apparatus. Through careful control of
the physical conditions of the machinery, essentially finished,
oxidation-reduction product may be extruded and used as-is or in
subsequently modified form.
[0086] In accordance with certain embodiments, a film of reactive
blend may be doctored onto a surface, such as stainless steel or
glass, and the film caused to undergo an oxidation-reduction
reaction. The resulting material can resemble a potato chip in
overall structure with variable porosity and other physical
properties.
[0087] In addition to the use of sponge material, the present
invention is also amenable to the use of other organic material
capable of imbibing reactive blend. Thus, if a gauze material is
used, the resulting oxidation reduction product assumes the form of
the gauze. A flannel material will give rise to a relatively thick
pad of inorganic material from which the organic residue may be
removed through the application of heat. Cotton or wool may be
employed as may be a host of other organic materials.
[0088] It is also possible to employ inorganic materials and even
metals in accordance with the present invention. Thus, inclusion of
conductive mesh, wires, or conductive polymers in materials which
form the substrate for the oxidation reduction of the reactive
blend can give rise to conductive, mineral-based products. Since
the minerals may be formed or modified to include a wide variety of
different elements, the same may be caused to be catalytic. The
combination of a porous, impermeable, catalytic material with
conductivity makes the present invention highly amenable to use in
fuel cells, catalytic converters, chemical reaction apparatus and
the like.
[0089] In this regard, since the conductive and compositional
character of the shaped bodies of the present invention may be
varied in accordance with preselected considerations, such shapes
may be used in electronic and military applications. Thus, the
ceramics of the invention may be piezoelectric, may be transparent
to microwave radiation and, hence, useful in radomes and the like.
They may be ion responsive and, therefore, useful as
electrochemical sensors, and in many other ways. The materials of
the invention may be formulated so as to act as pharmaceutical
excipients, especially when comminuted, as gas scrubber media, for
pharmaceutical drug delivery, in biotechnological fermentation
apparatus, in laboratory apparatus, and in a host of other
applications.
[0090] As will be apparent from a review of the chemistry portion
of the present specification, a very large variety of mineral
species may be formed. Each of these may be elaborated into shaped
bodies as described here and above. For example, transition metal
phosphates including those of scandium, titanium, chromium,
manganese, iron, cobalt, nickel, copper, and zinc may be elaborated
into pigments, phosphors, catalysts, electromagnetic couplers,
microwave couplers, inductive elements, zeolites, glasses, and
nuclear waste containment systems and coatings as well as many
others.
[0091] Rare earth phosphates can form intercalation complexes,
catalysts, glasses, ceramics, radiopharmaceuticals, pigments and
phosphors, medical imaging agents, nuclear waste solidification
media, electro-optic components, electronic ceramics, surface
modification materials and many others. Aluminium and zirconium
phosphates, for example, can give rise to surface protection
coatings, abrasive articles, polishing agents, cements, filtration
products and otherwise. Alkali and alkaline earth metal phosphates
are particularly amenable to low temperature glasses, ceramics,
biomaterials, cements, glass-metal sealing materials, glass-ceramic
materials including porcelains, dental glasses, electro-optical
glasses, laser glasses, specific refractive index glasses, optical
filters and the like.
[0092] In short, the combination of easy fabrication, great
variability in attainable shapes, low temperature elaboration, wide
chemical composition latitude, and the other beneficial properties
of the present invention lend it to a wide variety of applications.
Indeed, other applications will become apparent as the fill scope
of the present invention unfolds over time.
[0093] In accordance with the present invention, the minerals
formed hereby and the shaped bodies comprising them are useful in a
wide variety of industrial, medical, and other fields. Thus,
calcium phosphate minerals produced in accordance with preferred
embodiments of the present invention may be used in dental and
orthopaedic surgery for the restoration of bone, tooth material and
the like. The present minerals may also be used as precursors in
chemical and ceramic processing, and in a number of industrial
methodologies, such as crystal growth, ceramic processing, glass
making, catalysis, bioseparations, pharmaceutical excipients, gem
synthesis, and a host of other uses. Uniform microstructures of
unique compositions of minerals produced in accordance with the
present invention confer upon such minerals wide utility and great
"value added." Indeed, submicron microstructure can be employed by
products of the invention with the benefits which accompany such
microstructures.
[0094] Improved precursors provided by this invention yield lower
formation temperatures, accelerated phase transition kinetics,
greater compositional control, homogeneity, and flexibility when
used in chemical and ceramic processes. Additionally, these
chemically-derived, ceramic precursors have fine crystal size and
uniform morphology with subsequent potential for very closely
resembling or mimicking natural tissue structures found in the
body.
[0095] Controlled precipitation of specific phases from aqueous
solutions containing metal cations and phosphate anions represents
a difficult technical challenge. For systems containing calcium and
phosphate ions, the situation is further complicated by the
multiplicity of phases that may be involved in the crystallization
reactions as well as by the facile phase transformations that may
proceed during mineralization. The solution chemistry in aqueous
systems containing calcium and phosphate species has been
scrupulously investigated as a function of pH, temperature,
concentration, anion character, precipitation rate, digestion time,
etc. (P. Koutsoukos, Z. Amjad, M. B. Tomson, and G. H. Nancollas,
"Crystallization of calcium phosphates. A constant composition
study," J. Am. Chem. Soc. 102: 1553 (1980); A. T. C. Wong. and J.
T. Czernuszka, "Prediction of precipitation and transformation
behavior of calcium phosphate in aqueous media," in Hydroxyapatite
and Related Materials, pp 189-196 (1994), CRC Press, Inc.; G. H.
Nancollas, "In vitro studies of calcium phosphate crystallization,"
in Biomineralization--Chem- ical and Biochemical Perspectives, pp
157-187 (1989) ).
[0096] Solubility product considerations impose severe limitations
on the solution chemistry. Furthermore, methods for generating
specific calcium phosphate phases have been described in many
technical articles and patents (R. Z. LeGeros, "Preparation of
octacalcium phosphate (OCP): A direct fast method," Calcif. Tiss.
Int. 37: 194 (1985)). As discussed above, none of this
aforementioned art employs the present invention.
[0097] Several sparingly soluble calcium phosphate crystalline
phases, so called "basic" calcium phosphates, have been
characterized, including alpha- and beta-tricalcium phosphate
(.alpha.-TCP, .beta.-TCP, Ca.sub.3(PO.sub.4).sub.2, tetracalcium
phosphate (TTCP,Ca.sub.4(PO.sub.4)- .sub.2O), octacalcium phosphate
(OCP, Ca4H(PO.sub.4).sub.3.-nH.sub.20, where 2<n<3), and
calcium hydroxyapatite (HAp, Ca.sub.5(PO.sub.4).sub.3(OH)). Soluble
calcium phosphate phases, so called "acidic" calcium phosphate
crystalline phases, include dicalcium phosphate dihydrate (brushite
-DCPD, CaHPO.sub.4.H.sub.2O), dicalcium phosphate anhydrous
(monetite-DCPA, CaHPO.sub.4), monocalcium phosphate monohydrate
(MCPM, Ca(H.sub.2 PO.sub.4).sub.2-H.sub.2O), and monocalcium
phosphate anhydrous (MCPA, Ca(H.sub.2 PO.sub.4).sub.2). These
calcium phosphate compounds are of critical importance in the area
of bone cements and bone grafting materials. The use of DCPD, DCPA,
.alpha.-TCP, .beta.-TCP, TTCP, OCP, and HAp, alone or in
combination, has been well documented as biocompatible coatings,
fillers, cements, and bone-forming substances (F.C.M. Driessens, M.
G. Boltong, 0. Bermudez, J. A. Planell, M. P. Ginebra, and E.
Fernandez, "Effective formulations for the preparation of calcium
phosphate bone cements," J. Mat. Sci.: Mat. Med. 5: 164 (1994); R.
Z. LeGeros, "Biodegradation and bioresorption of calcium phosphate
ceramics," Clin. Mat. 14(1): 65 (1993); K. Ishikawa, S. Takagi, L.
C. Chow, and Y. Ishikawa, "Properties and mechanisms of
fast-setting calcium phosphate cements," J. Mat. Sci.: Mat. Med. 6:
528 (1995); A. A. Mirtchi, J. Lemaitre, and E. Munting, "Calcium
phosphate cements: Effect of fluorides on the setting and hardening
of beta-tricalcium phosphate--dicalcium phosphate--calcite
cements," Biomat. 12: 505 (1991); J. L. Lacout, "Calcium phosphate
as bioceramics," in Biomaterials - Hard Tissue Repair and
Replacement, pp 81-95 (1992), Elsevier Science Publishers).
[0098] Generally, these phases are obtained via thermal or
hydrothermal conversion of (a) solution-derived precursor calcium
phosphate materials, (b) physical blends of calcium salts, or (c)
natural coral. Thermal transformation of synthetic calcium
phosphate precursor compounds to TCP or TTCP is achieved via
traditional ceramic processing regimens at high temperature,
greater than about 800.degree. C. Thus, despite the various
synthetic pathways for producing calcium phosphate precursors, the
"basic" calcium phosphate materials used in the art
(Ca/P.gtoreq.1.5) have generally all been subjected to a high
temperature treatment, often for extensive periods of time. For
other preparations of "basic" calcium phosphate materials, see also
H. Monma, S. Ueno, and T. Kanazawa, "Properties of hydroxyapatite
prepared by the hydrolysis of tricalcium phosphate," J. Chem. Tech.
Biotechnol. 31: 15 (1981); H. Chaair, J. C. Heughebaert, and M.
Heughebaert, "Precipitation of stoichiometric apatitic tricalcium
phosphate prepared by a continuous process," J. Mater. Chem. 5(6):
895 (1995); R. Famery, N. Richard, and P. Boch, "Preparation of
alpha- and beta-tricalcium phosphate ceramics, with and without
magnesium addition," Ceram. Int. 20: 327 (1994); Y. Fukase, E. D.
Eanes, S. Takagi, L. C. Chow, and W. E. Brown, "Setting reactions
and compressive strengths of calcium phosphate cements," J. Dent.
Res. 69(12): 1852 (1990).
[0099] The present invention represents a significant departure
from prior methods for synthesizing metal phosphate minerals and
porous shaped bodies of these materials, particularly calcium
phosphate powders and materials, in that the materials are formed
from homogeneous solution using a novel Redox Precipitation
Reaction (RPR). They can be subsequently converted to TCP , HAp
and/or combinations thereof at modest temperatures and short firing
schedules. Furthermore, precipitation from homogeneous solution
(PFHS) in accordance with this invention, has been found to be a
means of producing particulates of uniform size and composition in
a form heretofore not observed in the prior art.
[0100] The use of hypophosphite [H.sub.2PO.sub.2.sup.-] anion as a
precursor to phosphate ion generation has been found to be
preferred since it circumvents many of the solubility constraints
imposed by conventional calcium phosphate precipitation chemistry
and, furthermore, it allows for uniform precipitation at high
solids levels. For example, reactions can be performed in
accordance with the invention giving rise to product slurries
having in excess of 30% solids. Nitrate anion is the preferred
oxidant, although other oxidizing agents are also useful.
[0101] The novel use of nitrate anion under strongly acidic
conditions as the oxidant for the hypophosphite to phosphate
reaction is beneficial from several viewpoints. Nitrate is readily
available and is an inexpensive oxidant. It passivates stainless
steel (type 316 SS) and is non-reactive to glass processing
equipment. Its oxidation byproducts (NO.sub.x) are manageable via
well-known pollution control technologies, and any residual nitrate
will be fugitive, as NO.sub.x under the thermal conversion schedule
to which the materials are usually subjected, thus leading to
exceedingly pure final materials.
[0102] Use of reagent grade metal nitrate salts and hypophosphorous
acid, as practiced in this invention, will lead to metal phosphate
phases of great purity.
[0103] Methods for producing usefull calcium phosphate-based
materials are achieved by reduction-oxidation precipitation
reactions (RPR) generally conducted at ambient pressure and
relatively low temperatures, usually below 250.degree. C. and
preferably below 200.degree. C., most preferably below 150.degree.
C. The manner of initiating such reactions is determined by the
starting raw materials, their treatment, and the redox
electrochemical interactions among them.
[0104] The driving force for the RPR is the concurrent reduction
and oxidation of anionic species derived from solution precursors.
Advantages of the starting solutions can be realized by the high
initial concentrations of ionic species, especially calcium and
phosphorus species. It has been found that the use of reduced
phosphorus compounds leads to solution stability at ionic
concentrations considerably greater than if fully oxidized
[PO.sub.4].sup.-3 species were used. Conventional processing art
uses fully oxidized phosphorus oxoanion compounds and is,
consequently, hindered by pH, solubility, and reaction temperature
constraints imposed by the phosphate anion.
[0105] Typical reducible species are preferably nitric acid,
nitrate salts (e.g. Ca(NO.sub.3).sub.24H.sub.2O), or any other
reducible nitrate compound, which is highly soluble in water. Other
reducible species include nitrous acid (HNO.sub.2) or nitrite
(NO.sub.2.sup.-) salts.
[0106] Among the oxidizable species which can be used are
hypophosphorous acid or hypophosphite salts [e.g.
Ca(H.sub.2PO.sub.2).sub.2] which are highly soluble in water. Other
oxidizable species which find utility include acids or salts of
phosphites (HPO.sub.3.sup.2-), pyrophosphites
(H.sub.2P.sub.2O.sub.5.sup.2-), thiosulfate
(S.sub.2O.sub.3.sup.2-), tetrathionate (S.sub.4O.sub.6.sup.2-),
dithionite (S.sub.2O.sub.4.sup.2-) trithionate
(S.sub.3O.sub.6.sup.2-), sulfite (SO.sub.3.sup.2-), and dithionate
(S.sub.2O.sub.6.sup.2-). In consideration of the complex inorganic
chemistry of the oxoanions of Groups 5B, 6B, and 7B elements, it is
anticipated that other examples of oxidizable anions can be
utilized in the spirit of this invention.
[0107] The cation introduced into the reaction mixture with either
or both of the oxidizing or reducing agents are preferably
oxidatively stable (i.e. in their highest oxidation state).
However, in certain preparations, or to effect certain reactions,
the cations may be introduced in a partially reduced oxidation
state. Under these circumstances, adjustment in the amount of the
oxidant will be necessary in order to compensate for the electrons
liberated during the oxidation of the cations during RPR.
[0108] It is well known in the art that for solutions in
equilibrium with ionic precipitates, the solute concentrations of
the reactant ions are dictated by solubility product relationships
and supersaturation limitations. For the
Ca.sup.2+-[PO.sub.4].sup.-3 system, these expressions are
exceedingly complicated, due in large part to the numerous pathways
(i.e., solid phases) for relieving the supersaturation conditions.
Temperature, pH, ionic strength, ion pair formation, the presence
of extraneous cations and anions all can affect the various solute
species equilibria and attainable or sustainable supersaturation
levels (F. Abbona, M. Franchini-Angela, and R. Boistelle,
"Crystallization of calcium and magnesium phosphates from solutions
of medium and low concentrations," Cryst. Res. Technol. 27: 41
(1992); G. H. Nancollas, "The involvement of calcium phosphates in
biological mineralization and demineralization processes," Pure
Appl. Chem. 64(11): 1673 (1992); G. H. Nancollas and J. Zhang,
"Formation and dissolution mechanisms of calcium phosphates in
aqueous systems," in Hydroxyapatite and Related Materials, pp 73-81
(1994), CRC Press, Inc.; P. W. Brown, N. Hocker, and S. Hoyle,
"Variations in solution chemistry during the low temperature
formation of hydroxyapatite," J. Am. Ceram. Soc. 74(8): 1848
(1991); G. Vereecke and J. Lemaitre, "Calculation of the solubility
diagrams in the system
Ca(OH).sub.2--H.sub.3PO.sub.4--KOH--HNO.sub.3--CO.-
sub.2--H.sub.2O, " J. Cryst. Growth 104: 820 (1990); A. T. C. Wong
and J. T. Czernuszka, "Prediction of precipitation and
transformation behavior of calcium phosphate in aqueous media," in
Hydroxyapatite and Related Materials, pp 189-196 (1994), CRC Press,
Inc.; G. H. Nancollas, "In vitro studies of calcium phosphate
crystallization," in Biomineralization--Chem- ical and Biochemical
Perspectives, pp 157-187 (1989)).
[0109] Additionally, while thermodynamics will determine whether a
particular reaction is possible, kinetic effects may be very much
more important in explaining the absence or presence of particular
calcium phosphate phases during precipitation reactions.
[0110] In the practice of certain preferred embodiments of this
invention to give rise to calcium phosphates, soluble calcium ion
is maintained at concentrations of several molar in the presence of
soluble hypophosphite anion which is, itself, also at high molar
concentrations. The solution is also at a very low pH due to the
presence of nitric and hypophosphorous acids. Indeed, such
solutions of calcium and hypophosphite ions can be stable
indefinitely with respect to precipitation, at room temperature or
below. In contrast, it is impossible (in the absence of ion
complexation or chelating agents) to simultaneously maintain
calcium ions and phosphate anions at similar concentrations as a
solid phase would immediately precipitate to relieve the
supersaturation. Upon oxidation of the hypophosphite ion to
phosphite and, subsequently, to phosphate, calcium phosphate phases
are rapidly precipitated from homogeneous solution under solution
conditions unique (concentration, pH, ionic strength) for the
formation of such materials. The combination of homogeneous
generation of precipitating anion, rapid precipitation kinetics,
and unique thermodynamic regime results in the formation of calcium
phosphate precursors having unique size and morphological
characteristics, surface properties, and reactivities.
[0111] The foregoing consideration will also apply to minerals
other than the calcium phosphates. Perforce, however, the phase
diagrams, equilibrium conditions and constituent mineral phases
will differ in each family of minerals.
[0112] Uniformly sized and shaped particles of metal salts
comprised of one or more metal cations in combination with one or
more oxoacid anions can result from the present general method for
the controlled precipitation of said metal salts from aqueous
solutions. These proceed via the in situ homogeneous production of
simple or complex oxoacid anions of one or more of the nonmetallic
elements, Group 5B and 6B (chalcogenides), and 7B (halides). The
first oxoacid anion undergoes oxidation (increase in chemical
oxidation state) to generate the precipitant anionic species along
with concurrent reduction (decrease in chemical oxidation state) of
the nonmetallic element of a second, dissimilar oxoacid anion, all
oxoacid anions initially being present in solution with one or more
metal cations known to form insoluble salts with the precipitant
anion. The metal cations are, preferably, oxidatively stable, but
may undergo oxidation state changes themselves under certain
conditions.
[0113] RPR is induced preferably by heating a homogeneous solution,
so as to promote the onset and continuation of an exothermic redox
reaction. This exothermic reaction results in the generation of
gases, usually various nitrogen oxide gases such as NOX, where
0.5<x <2, as the soluble reduced phosphorus species are
converted to precipitating anions which then homogeneously
precipitate the calcium ions from the reaction medium. At this
stage, the reaction is substantially complete, resulting in an
assemblage of ultrafine precipitated particles of the predetermined
calcium-phosphate stoichiometry. The reaction yield is high as is
the purity of the reaction products.
[0114] The use of alternate heating methods to initiate and
complete the RPR reaction may offer utility in the formation of
scaffold structures. One such power source is microwave energy, as
found in conventional 600-1400 W home microwave ovens. The benefit
of the use of microwaves is the uniformity of the heating
throughout the entire reaction mass and volume as opposed to the
external-to-internal, thermal gradient created from traditional
conduction/convection/radiant heating means. The rapid, internal,
uniform heating condition created by the use of microwave energy
provides for rapid redox reaction initiation and drying. The excess
RPR liquid is expelled to the outer surface of the cellulose body
and flashes off to form an easily removed deposit on the surface.
The rapid rate of heating and complete removal of the fugitive
substructure alters the particulate structure resulting in greater
integral strength. The speed of heating and initiation of the RPR
reaction may also minimize crystal grain growth.
[0115] Intermediate precursor mineral powders are homogeneously
precipitated from solution. Moderate heat treatments at
temperatures <500.degree. C., can be used to further the
transformation to various phosphate containing phases. Proper
manipulations of chemistry and process conditions have led to mono-
and multiphasic compounds with unique crystal morphologies, see,
e.g. FIGS. 1 and 2.
[0116] The nitrate/hypophosphite redox system involves a
hypophosphite oxidation to phosphate (P.sup.+1 to P.sup.+5, a
4e.sup.- oxidation) as depicted in the following equations
(E.sub.0/V from N. N. Greenwood and A. Earnshaw, "Oxoacids of
phosphorus and their salts," in Chemistry of the Elements, pp
586-595 (1984), Pergamon Press):
1 Reduction potential at pH 0, 25.degree. C. Reaction E.sub.0/V
H.sub.3PO.sub.3 + 2H.sup.+ + 2e.sup.- = H.sub.3PO.sub.2 + H.sub.2O
-0.499 (1) H.sub.3PO.sub.4 + 2H.sup.+ + 2e.sup.- = H.sub.3PO.sub.3
+ H.sub.2O -0.276 (2) H.sub.3PO.sub.4 + 4H.sup.+ + 4e.sup.- =
H.sub.3PO.sub.2 + H.sub.2O -0.775 Overall (3)
[0117] and a nitrate reduction to NO.sub.x (N.sup.+5 to N.sup.+3 or
N.sup.+2, either a 2e.sup.- or a 3e.sup.- reduction) as depicted in
the following equations:
2 Reduction potential at pH 0, 25.degree. C. Reaction E.sub.0/V
2NO.sub.3.sup.- + 4H.sup.+ 2e.sup.- = N.sub.2O.sub.4 + 2H.sub.2O
0.803 (4) NO.sub.3.sup.- + 3H.sup.+ + 2e.sup.- = HNO.sub.2 +
H.sub.2O 0.94 (5) NO.sub.3 + 4H.sup.+ + 3e.sup.- = NO + 2H.sub.2O
0.957 (6)
[0118] Chemical reactions are conveniently expressed as the sum of
two (or more) electrochemical half-reactions in which electrons are
transferred from one chemical species to another. According to
electrochemical convention, the overall reaction is represented as
an equilibrium in which the forward reaction is stated as a
reduction (addition of electrons), i.e.:
Oxidized species+ne.sup.-=Reduced species
[0119] For the indicated equations at pH=0 and 25.degree. C., the
reaction is spontaneous from left to right if E.sub.0 (the
reduction potential) is greater than 0, and spontaneous in the
reverse direction if E.sub.0 is less than 0.
[0120] From the above reactions and associated electrochemical
potentials, it is apparent that nitrate is a strong oxidant capable
of oxidizing hypophosphite (P.sup.+1) to phosphite (P.sup.+3) or to
phosphate (P.sup.+5) regardless of the reduction reaction pathway,
i.e., whether the reduction process occurs according to Equation 4,
5, or 6. If an overall reaction pathway is assumed to involve a
combination of oxidation reaction (Eq.3) (4e.sup.- exchange) and
reduction reaction (Eq.6) (3e.sup.- exchange), one can calculate
that in order for the redox reaction to proceed to completion, 4/3
mole of NO.sub.3.sup.- must be reduced to NO per mole of
hypophosphite ion to provide sufficient electrons. It is obvious to
one skilled in the art that other redox processes can occur
involving combinations of the stated oxidation and reduction
reactions.
[0121] Different pairings of oxidation and reduction reactions can
be used to generate products according to the spirit of this
invention. Indeed, the invention generally allows for the in situ
homogeneous production of simple or complex oxoacid anions in
aqueous solution in which one or more nonmetallic elements such as
Group 5B and 6B (chalcogenides), and 7B (halides) comprising the
first oxoacid anion undergoes oxidation to generate the precipitant
anionic species along with concurrent reduction of the nonmetallic
element of a second, dissimilar oxoacid anion.
[0122] In each of the above scenarios, the key is the
reduction-oxidation reaction at high ionic concentrations leading
to the homogenous precipitation from solution of novel calcium
phosphate powders. Never before in the literature has the ability
to form such phases, especially calcium-phosphate phases, been
reported under the conditions described in this invention.
[0123] Specific embodiments of the invention utilize the
aforementioned processes to yield unique calcium phosphate
precursor minerals that can be used to form a self-setting cement
or paste. Once placed in the body, these calcium phosphate cements
(CPC) will be resorbed and remodeled (converted) to bone. A single
powder consisting of biphasic minerals of varying Ca/P ratio can be
mixed to yield self-setting pastes that convert to type-B
carbonated apatite (bone mineral precursor) in vivo.
[0124] The remodeling behavior of a calcium phosphate bioceramic to
bone is dictated by the energetics of the surface of the ceramic
and the resultant interactions with osteoclastic cells on approach
to the interface. Unique microstructures can yield accelerated
reactivity and, ultimately, faster remodeling in vivo. The
compositional flexibility in the fine particles of this invention
offers adjustable reactivity in vivo. The crystallite size and
surface properties of the resultant embodiments of this invention
are more similar to the scale expected and familiar to the cells
found in the body. Mixtures of powders derived from the processes
of this invention have tremendous utility as calcium phosphate
cements (CPCs).
[0125] An aqueous solution can be prepared in accordance with the
present invention and can be imbibed into a sacrificial organic
substrate of desired shape and porosity, such as a cellulose
sponge. The solution-soaked substrate is subjected to controlled
temperature conditions to initiate the redox precipitation
reaction. After the redox precipitation reaction is complete, a
subsequent heating step is employed to combust any remaining
organic material and/or promote phase changes. The resultant
product is a porous, inorganic material which mimics the shape,
porosity and other aspects of the morphology of the organic
substrate.
[0126] It is anticipated that the porous inorganic materials of the
present invention would be suitable for a variety of applications.
FIG. 3 depicts a discoidal filter scaffold 16, which is prepared in
accordance with the present invention, and enclosed within an
exterior filter housing 18 for filtration or bioseparation
applications. Depending upon its end use, discoidal filter scaffold
16 can be a biologically active, impregnated porous scaffold. Arrow
20 represents the inlet flow stream. Arrow 22 represents the
process outlet stream after passing through discoidal filter
scaffold 16.
[0127] FIG. 4 illustrates a block of the porous inorganic material
that is used as a catalyst support within a two stage, three way
hot gas reactor or diffusor. Items 30 and 32 illustrate blocks of
the porous material used as catalytically impregnated scaffolds.
Items 30 and 32 may be composed of the same or different material.
Both 30 and 32, however, are prepared in accordance with an
embodiment of the present invention. Item 34 depicts the first
stage catalyst housing, which may be comprised of a
ferrous-containing material, and encloses item 30. Item 36 depicts
the second stage catalyst housing, which may be comprised of a
ferrous-containing material, and encloses item 32. Item 38
represents the connector pipe, which is comprised of the same
material as the housings 34 and 36, and connects both 34 and 36.
Arrow 40 represents the raw gas inlet stream prior to passing
through both blocks of catalytically impregnated scaffold (items 30
and 32). Arrow 42, lastly, represents the processed exhaust gas
stream.
[0128] In other embodiments of the present invention, the inorganic
porous material is a calcium phosphate scaffolding material that
may be employed for a variety of uses. FIG. 5 illustrates a block
of the calcium phosphate scaffolding material 55 that may be
inserted into a human femur and used for cell seeding, drug
delivery, protein adsorption, growth factor introduction or other
biomedical applications. Femoral bone 51 is comprised of metaphysis
52, Haversian canal 53, diaphysis 54 and cortical bone 56. The
calcium phosphate scaffolding material 55 is inserted into an
excavation of the femoral bone as shown and ties into the Haversian
canal allowing cell seeding, drug delivery, or other applications.
Scaffolding material 55 can be used in the same manner in a variety
of human or mammalian bones.
[0129] FIG. 6A shows the calcium phosphate material of the present
invention formed into the shape of a calcium phosphate sleeve 60.
Item 62 depicts the excavated cavity which can be formed via
machining or other means. Item 64 presents a plurality of threads
which can be coated with bioactive bone cement. FIG. 6B shows the
calcium phosphate sleeve 60 inserted into the jaw bone 66 and gum
67. The calcium phosphate sleeve 60 may be fixed in place via pins,
bone cement, or other mechanical means of adhesion. An artificial
tooth or dental implant 68 can then be screwed into sleeve 60 by
engaging threads 64.
[0130] FIG. 7A shows the porous, calcium phosphate scaffolding
material 70, prepared in accordance with an embodiment of the
present invention, which is machined or molded to patient specific
dimensions. FIG. 7B depicts the use of the material 70 that is
formed into the shape of craniomaxillofacial implant 76, a
zygomatic reconstruction 72, or a mandibular implant 74.
[0131] FIG. 8A depicts a plug of the porous, calcium phosphate
scaffolding material 80. FIG. 8B illustrates plug 80 which is
inserted into an excavation site 83 within a human knee, below the
femur 81 and above the tibia 82, for use in a tibial plateau
reconstruction. Plug 80 is held in place or stabilized via a bone
cement layer 84.
[0132] FIG. 9 shows the calcium phosphate scaffolding material
within a human femur that is used as a block 92 for bulk
restoration or repair of bulk defects in metaphyseal bone or
oncology defects, or as a sleeve 94 for an orthopaedic screw, rod
or pin 98 augmentation. Item 99 depicts an orthopaedic plate
anchored by the orthopaedic device item 98. Bone cement layer 96
surrounds and supports sleeve 94 in place.
[0133] Lastly, FIGS. 10A and 10B depict the use of the calcium
phosphate scaffolding material as a receptacle sleeve 100 that is
inserted into the body to facilitate a bipolar hip replacement.
Cavity 102 is machined to accommodate the insertion of a metallic
ball joint implant or prosthesis 103. An orthopaedic surgeon drills
a cavity or furrow into the bone 101 to receive sleeve 100. Sleeve
100 is then affixed to the surrounding bone via a bioactive or
biocompatible bone cement layer 104 or other means. On the
acetabular side, a femoral head articulation surface 106 is
cemented to a bone cement layer 104 that resides within a prepared
cavity with material of the present invention, 100. A high
molecular weight polyethylene cup, 105 is used to facilitate
articulation with the head of the prosthesis 103. The metallic ball
joint implant or prosthesis 103 is thus inserted into a high
molecular weight polyethylene cup 105 to facilitate joint
movement.
[0134] Orthopaedic appliances such as joints, rods, pins, sleeves
or screws for orthopaedic surgery, plates, sheets, and a number of
other shapes may be formed from the calcium phosphate scaffolding
material in and of itself or used in conjunction with conventional
appliances that are known in the art. Such porous inorganic bodies
can be bioactive and can be used, preferably, in conjunction with
biocompatible gels, pastes, cements or fluids and surgical
techniques that are known in the art. Thus, a screw or pin can be
inserted into a broken bone in the same way that metal screws and
pins are currently inserted, using conventional bone cements or
restoratives in accordance with the present invention or otherwise.
The bioactivity of the calcium phosphate scaffolding material will
give rise to osteogenesis with beneficial medical or surgical
results. For example, calcium phosphate particles and/or shaped
bodies prepared in accordance with this invention can be used in
any of the orthopaedic or dental procedures known for the use of
calcium phosphate; the procedures of bone filling defect repair,
oncological defect filling, craniomaxillofacial void filling and
reconstruction, dental extraction site filling, and potential drug
delivery applications.
[0135] The scaffold structures of this invention, calcium phosphate
in particular, can be imbibed with blood, cells (e.g. fibroblasts,
mesenchymal, stromal, marrow and stem cells), protein rich plasma
other biological fluids and any combination of the above.
Experiments have been conducted with ovine and canine blood
(37.degree. C.) showing the ability of the scaffold to maintain its
integrity while absorbing the blood into its pores. This capability
has utility in cell-seeding, drug delivery, and delivery of
biologic molecules as well as in the application of bone tissue
engineering, orthopaedics, and carriers of pharmaceuticals. This
makes the Ca-P scaffold ideal for the use as an autograft extender
or replacement graft material.
[0136] The scaffold structures, especially calcium phosphate, can
be imbibed with any bioabsorbable polymer or film-forming agent
such as polycaprolactones (PCL), polyglycolic acid (PGA),
poly-L-Lactic acid (PL-LA), polysulfones, polyolefins, polyvinyl
alcohol (PVA), polyalkenoics, polyacrylic acids (PAA), polyesters
and the like. Experiments have been conducted with PCL, by
solubilizing the PCL in an evaporative solvent and saturating a
plug of calcium phosphate scaffold structure, allowing the
structure to dry, and thus fixing the PCL onto the surface and
throughout the body of the scaffold. The resultant mass is strong,
carveable, and somewhat compressible. Experiments showed that the
PCL coated material still absorbs blood.
[0137] Numerous other uses for these minerals and shaped bodies
comprised thereof are anticipated. The oxidizing agents, reducing
agents, ratios, co-reactants and other adducts, products and
exemplary uses will be understood by inorganic chemists from a
review of the aforementioned chemical reactions. Calcium phosphates
are indicated for biological restorations, dental restorations,
bioseparations media, and ion or protein chromatography. Transition
metal phosphates (Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) and
shaped, porous articles thereof have numerous potential uses as
pigments, phosphors, catalysts, electromagnetic couplers, microwave
couplers, inductive elements, zeolites, glasses, nuclear waste
containment systems, radomes and coatings. Addition of rare-earths
phosphates can lead to uses as intercalation compounds, catalysts,
catalyst support material, glasses and ceramics,
radiopharmaceuticals, pigments and phosphors, medical imaging
agents, nuclear waste solidification, electro-optics, electronic
ceramics, and surface modifications.
[0138] Aluminum and zirconium phosphates and shaped, porous
articles thereof are ideal candidates for surface protective
coatings, abrasive particles, polishing agents, cements, and
filtration products in either granular form or as coatings. The
alkali (Na, K, Rb, Cs) and alkaline-earth (Be, Mg, Ca, Sr, Ba)
phosphates and shaped, porous articles thereof would generate ideal
low temperature glasses, ceramics, biomaterials, cements, glass to
metal seals, and other numerous glass-ceramic materials, such as
porcelains, dental glasses, electro-optic glasses, laser glasses,
specific refractive index glasses and optical filters.
[0139] It is to be understood that the diverse chemistries set
forth herein may be applied to the creation of shaped bodies of the
invention.
EXAMPLES
Example 1
Low Temperature Calcium Phosphate Powders
[0140] An aqueous solution of 8.51 g 50 wt % hypophosphorous acid,
H.sub.3PO.sub.2 (Alfa/Aesar reagent #14142, CAS #6303-21-5),
equivalent to 71.95 wt % [PO.sub.4].sup.-3 was combined with 8.00 g
distilled water to form a clear, colorless solution contained in a
250 ml Pyrex beaker. To this solution was added 22.85 g calcium
nitrate tetrahydrate salt, Ca(NO.sub.3).sub.2.4H.sub.2O (ACS
reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4),
equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in
this mixture was 3/2 and the equivalent solids level [as
Ca.sub.3(PO.sub.4).sub.2] was 25.4 wt %. Endothermic dissolution of
the calcium nitrate tetrahydrate proceeded under ambient
temperature conditions, eventually forming a homogeneous solution.
Warming of this solution above 25.degree. C. initiated a reaction
in which the solution vigorously bubbled while evolving red-brown
acrid fumes characteristic of NO.sub.x(g). The sample turned into a
white, pasty mass which foamed and pulsed with periodic expulsion
of NO.sub.x(g). After approximately two minutes, the reaction was
essentially complete, leaving a white, pasty mass which was warm to
the touch. After cooling to room temperature, the solid (A) was
stored in a polyethylene vial.
[0141] Three days after its preparation, a few grams of the damp,
pasty solid were immersed in 30 ml distilled water in order to
"wash out" any unreacted, water soluble components. The solid was
masticated with a spatula in order to maximize solid exposure to
the water. After approximately 15 minutes, the solid was recovered
on filter paper and the damp solid (B) stored in a polyethylene
vial.
[0142] X-ray diffraction (XRD) patterns were obtained from packed
powder samples using the Cu-K.alpha. line (.lambda.=1.7889
Angstrom) from a Rigaku Geigerflex instrument (Rigaku/USA, Inc.,
Danvers, Mass. 01923) run at 45 kV/30 mA using a 2 degree/minute
scan rate over the 2.theta. angular range from 15-50.degree. or
broader. Samples were run either as prepared or following heat
treatment in air in either a Thermolyne type 47900 or a Ney model
3-550 laboratory furnace. XRD analysis of the samples yielded the
following results:
3 Heat Major Minor Sample treatment phase phase Unwashed As
prepared Undetermined -- (A) Unwashed 300.degree. C., 1 hour
Monetite [CaHPO.sub.4] -- (A) Unwashed 500.degree. C., 1 hour
Whitlockite [.beta.-Ca.sub.3(PO.sub.4).- sub.2]
CaH.sub.2P.sub.2O.sub.7 (A) Unwashed 700.degree. C., 1 hour
Whitlockite [.beta.-Ca.sub.3(PO.sub.4).sub.2] + (A)
HAp[Ca.sub.5(PO.sub.4).sub.3(OH)] Washed (B) As prepared Monetite
[CaHPO.sub.4] Washed (B) 100.degree. C., 1 hour Monetite
[CaHPO.sub.4]
[0143] Additional amounts of NO.sub.x(g) were evolved during firing
of the samples at or above 300.degree. C.
[0144] A sample of the powder produced according to this Example
was submitted to an outside laboratory for analysis (Coming, Inc.,
CELS-Laboratory Services, Coming, N.Y. 14831). The results of this
outside lab analysis confirmed that the powder fired at 700.degree.
C. was comprised of whitlockite and hydroxyapatite.
Example 2
Low Temperature Calcium Phosphate Powder
[0145] Example 1 was repeated using five times the indicated
weights of reagents. The reactants were contained in a 5-1/2"
diameter Pyrex crystallizing dish on a hotplate with no agitation.
Warming of the homogeneous reactant solution above 25.degree. C.
initiated an exothermic reaction which evolved red-brown acrid
fumes characteristic of NO.sub.x(g). Within a few seconds following
onset of the reaction, the sample turned into a white, pasty mass
which continued to expel NO.sub.x(g) for several minutes. After
approximately five minutes, the reaction was essentially complete
leaving a damp solid mass which was hot to the touch. This solid
was cooled to room temperature under ambient conditions for
approximately 20 minutes and divided into two portions prior to
heat treatment.
[0146] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air, XRD indicated the fired solids to be composed of:
4 Heat Major Minor Sample treatment phase phase A 500.degree. C., 1
hour Whitlockite HAp[Ca.sub.5(PO.sub.4).su- b.3(OH)]
[.beta.-Ca.sub.3(PO.sub.4).sub.2] B 700.degree. C., 1 hour HAp
Whitlockite [.beta.-Ca.sub.3(PO.sub.4).sub.2]
[Ca.sub.5(PO.sub.4).sub.3(OH)]
Example 3
Low Temperature Calcium Phosphate Powders
[0147] An aqueous solution of 8.51 g 50 wt % H.sub.3PO.sub.2 was
combined with 8.00 g of 25.0 wt % aqueous solution of calcium
acetate monohydrate, Ca(O.sub.2CCH.sub.3).sub.2.H.sub.2O (ACS
reagent, Aldrich Chemical Co., Inc. #40,285-0, CAS 5743-26-0),
equivalent to 5.69 wt % Ca, to give a clear, colorless solution
contained in a 250 ml Pyrex beaker. To this solution was added
20.17 g Ca(NO.sub.3).sub.2.4H.sub.2O salt. The molar ratio of
Ca/phosphate in this mixture was 3/2 and the equivalent solids
level [as Ca.sub.3(PO.sub.4).sub.2] was 27.3 wt %. Endothermic
dissolution of the calcium nitrate tetrahydrate salt proceeded
giving a homogeneous solution once the sample warmed to room
temperature. Further warming of this solution to >25.degree. C.
on a hotplate initiated a reaction which proceeded as described in
Example 1. After approximately three minutes, the reaction was
essentially complete leaving a moist, white, crumbly solid which
was hot to the touch and which smelled of acetic acid. After
cooling to room temperature, the solid was stored in a polyethylene
vial.
[0148] Heat treatment and X-ray diffraction analysis of this solid
were conducted as described in Example 1. Following heat treatment
in air at 500.degree. C. for either 0.5 or 1 hour, XRD indicated
the solid to be composed of whitlockite as the primary phase along
with hydroxylapatite as the secondary phase. XRD results indicate
that the relative ratio of the two calcium phosphate phases was
dependent on the duration of the heat treatment and the presence of
the acetate anion, but no attempts were made to quantify the
dependence.
5 Heated to 500.degree. C.,1 hour (Major) Whitlockite
[.beta.-Ca.sub.3(PO.sub.4).sub.2] (minor) Ca.sub.5(PO.sub.4).sub.-
3-x(CO.sub.3).sub.x(OH)
[0149] Comparing the XRD spectra from these results in Example 3
with XRD spectra from Example I shows the difference in the amount
of HAp- Ca.sub.5(PO.sub.4).sub.3-x(CO.sub.3).sub.x(OH) phase
present for each minor phase. The samples in Example 1 exhibited no
acetate whereas the samples in Example 3 showed acetate present.
This is indicative of the counteranion effect on crystal
formation.
[0150] Fourier Transform Infrared (FTIR) spectra were obtained
using a Nicolet model 5DXC instrument (Nicolet Instrument Co., 5225
Verona Rd. Madison, Wis. 53744) run in the diffuse reflectance mode
over the range of 400 to 4000 cm.sup.-1. The presence of the
carbonated form of HAp is confirmed by the FTIR spectra, which
indicated the presence of peaks characteristic of [PO.sub.4].sup.-3
(580-600, 950-1250 cm.sup.-1) and of [CO.sub.3].sup.-2 (880, 1400,
& 1450 cm.sup.-1). The P.dbd.O stretch, indicated by the strong
peak at 1150-1250 cm.sup.-1, suggests a structural perturbation of
hydroxyapatite by the carbonate ion.
Example 4
Colloidal SiO.sub.2 Added to Calcium Phosphate Mixtures via
RPR.
[0151] An aliquot of 8.00g 34.0 wt % SiO.sub.2 hydrosol (Nalco
Chemical Co., Inc. #1034A, batch #B5G453C) was slowly added to 8.51
g 50 wt % aqueous solution of H.sub.3PO.sub.2 with rapid stirring
to give a homogeneous, weakly turbid colloidal dispersion. To this
dispersion was added 22.85 g Ca(NO.sub.3).sub.2.4H.sub.2O salt such
that the molar ratio of calcium/phosphate in the mixture was 3/2.
Endothermic dissolution of the calcium nitrate tetrahydrate
proceeded giving a homogeneous colloidal dispersion once the sample
warmed to room temperature. The colloidal SiO.sub.2 was not
flocculated despite the high acidity and ionic strength in the
sample. Warming of the sample on a hotplate to >25.degree. C.
initiated a reaction as described in Example 1. The resultant
white, pasty solid was stored in a polyethylene vial.
[0152] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air at 500.degree. C. for 1.0 hour, XRD indicated the solid to be
composed of whitlockite plus hydroxyapatite.
6 Heated to 300.degree. C., 2 hours (Major) Calcium pyrophosphate
[Ca.sub.2P.sub.2O.sub.7] (minor) Octacalcium phosphate
[Ca.sub.4H(PO.sub.4).sub.3 .multidot. 2H.sub.2O] Heated to
500.degree. C., 1 hour (Major) Whitlockite
[b-Ca.sub.3(PO.sub.4).sub.2] (minor) HAp [Ca.sub.5(PO.sub.4).sub.3-
(OH)]
Example 5
Low Temperature Calcium Phosphate Powder
[0153] Example 1 was repeated with the addition of 1 0.00g
dicalcium phosphate dihydrate, DCPD, CaHPO4.2H.sub.2O (Aldrich
Chemical Co., Inc. #30,765-3, CAS #7789-77-7) to the homogeneous
solution following endothermic dissolution of the calcium nitrate
salt. The DCPD was present both as suspended solids and as
precipitated material (no agitation used). Warming of the sample to
>25.degree. C. initiated an exothermic reaction as described in
Example 1, resulting in the formation of a white, pasty solid. Heat
treatment and X-ray diffraction of this solid were conducted as
described in Example 1. Following heat treatment in air at
500.degree. C. for 1 hour, XRD indicated the solid to be composed
of whitlockite as the primary phase along with calcium
pyrophosphate (Ca.sub.2P.sub.2O.sub.7) as the secondary phase.
7 Heated to 500.degree. C., 1 hour (Major) Whitlockite
[.beta.-Ca.sub.3(PO.sub.4).sub.2] (minor)
Ca.sub.2P.sub.2O.sub.7
Example 6
Low Temperature Zinc Phosphate Powder Preparation
[0154] An aqueous solution of 8.51 g 50 wt % H.sub.3PO.sub.2 in
8.00 g distilled water was prepared as described in Example 1. To
this solution was added 28.78 g zinc nitrate hexahydrate salt,
Zn(NO.sub.3).sub.2.6H.su- b.2O (ACS reagent, Aldrich Chemical Co.,
Inc. #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt % Zn. The
molar ratio of Zn/phosphate in this mixture was 3/2 and the
equivalent solids level [as Zn.sub.3(PO.sub.4).sub.2] was 27.5 wt
%. Endothermic dissolution of the zinc nitrate hexahydrate
proceeded giving a homogeneous solution once the sample warmed to
room temperature. Further warming of this solution to
>25.degree. C. on a hotplate initiated a reaction in which the
solution vigorously evolved red-brown acrid fumes of NO.sub.x(g).
The reaction continued for approximately 10 minutes while the
sample remained a clear, colorless solution, abated somewhat for a
period of five minutes, then vigorously resumed finally resulting
in the formation of a mass of moist white solid, some of which was
very adherent to the walls of the Pyrex beaker used as a reaction
vessel. The hot solid was allowed to cool to room temperature and
was stored in a polyethylene vial.
[0155] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air at 500.degree. C. for 1 hour, XRD indicated the solid to be
composed of Zn.sub.3(PO.sub.4).sub.2 (PDF 30-1490).
[0156] Heated to 500.degree. C., 1 hour (Major)
Zn.sub.3(PO.sub.4).sub.2
Example 7
Low Temperature Iron Phosphate Powders
[0157] An aqueous solution of 17.50 g 50 wt % H.sub.3PO.sub.2 was
combined with 15.00 g distilled water to form a clear, colorless
solution contained in a 250 ml Pyrex beaker on a hotplate/stirrer.
To this solution was added 53.59 g ferric nitrate nonahydrate salt,
Fe(NO.sub.3).sub.3-9H.sub.2O (ACS reagent, Alfa/Aesar reagent
#33315, CAS #7782-61-8), equivalent to 13.82 wt % Fe. The molar
ratio of Fe/phosphate in this mixture was 1/1 and the equivalent
solids level [as FePO.sub.4] was 23.2 wt %. Endothermic dissolution
of the ferric nitrate nonahydrate salt proceeded partially with
gradual warming of the reaction mixture, eventually forming a pale
lavender solution plus undissolved salt. At some temperature
>25.degree. C., an exothermic reaction was initiated which
evolved NO.sub.x(g). This reaction continued for approximately 15
minutes during which time the reaction mixture became syrup-like in
viscosity. With continued reaction, some pale yellow solid began to
form at the bottom of the beaker. After approximately 40 minutes of
reaction, the sample was allowed to cool to room temperature. The
product consisted of an inhomogeneous mixture of low density yellow
solid at the top of the beaker, a brown liquid with the consistency
of caramel at the center of the product mass, and a sand colored
solid at the bottom of the beaker. The solids were collected as
separate samples insofar as was possible.
[0158] Heat treatment and X-ray diffraction of the solid collected
from the top of the beaker were conducted as described in Example
1. Following heat treatment in air at 500.degree. C. for 1 hour,
XRD indicated the solid to be composed of graftonite
[Fe.sub.3(PO.sub.4).sub.2] (PDF 27-0250) plus some amorphous
material, suggesting that the heat treatment was not sufficient to
induce complete sample crystallization as illustrated below:
[0159] Heated to 500.degree. C., 1 hour (Major) Graftonite
[Fe.sub.3(PO.sub.4).sub.2]
[0160] Some mechanism apparently occurs by which Fe.sup.3+ was
reduced to Fe.sup.2+.
Example 8
Low Temperature Calcium Phosphate Powders
[0161] An aqueous solution of 19.41 g 50 wt % H.sub.3PO.sub.2 was
combined with 5.00 g distilled water to form a clear, colorless
solution contained in a 250 ml Pyrex beaker. To this solution was
added 34.72 g Ca(NO.sub.3).sub.2.4H.sub.2O. The molar ratio of
Ca/phosphate in this mixture was 1/1 and the equivalent solids
level [as CaHPO.sub.4] was 33.8 wt %. Endothermic dissolution of
the calcium nitrate tetrahydrate proceeded under ambient
temperature conditions, eventually forming a homogeneous solution
once the sample warmed to room temperature. Warming of this
solution above 25.degree. C. initiated a vigorous exothermic
reaction which resulted in the evolution of NO.sub.x(g), rapid
temperature increase of the sample to >100.degree. C., and
extensive foaming of the reaction mixture over the beaker rim,
presumably due to flash boiling of water at the high reaction
temperature. After cooling to room temperature, the reaction
product was collected as a dry, white foam which was consolidated
by crushing to a powder.
[0162] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Results are as follows:
8 Heated to 300.degree. C., 2 hours (Major) Ca.sub.2P.sub.2O.sub.7
(minor) Octacalcium phosphate [Ca.sub.4H(PO.sub.4).sub.3-2H.sub.2O]
Heated to 500.degree. C., 1 hour (Major) Ca.sub.2P.sub.2O.sub.7
Example 9
Low Temperature Calcium Phosphate Powders
[0163] Example 3 was repeated using ten times the indicated weights
of reagents. The reactants were contained in a 5-1/2" diameter
Pyrex crystallizing dish on a hotplate/stirrer. The reactants were
stirred continuously during the dissolution and reaction stages.
The chemical reaction initiated by heating the solution to
>25.degree. C. resulted in the evolution of NO.sub.x(g) for
several minutes with no apparent effect on the stability of the
system, i.e. the solution remained clear and colorless with no
evidence of solid formation. After abating for several minutes, the
reaction resumed with increased intensity resulting in the
voluminous generation of NO.sub.x(g) and the rapid appearance of a
pasty white solid material. The reaction vessel and product were
both hot from the reaction exotherm. The product was cooled in air
to a white crumbly solid which was stored in a polyethylene
vial.
[0164] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air at 500.degree. C. for either 0.5 or 1 hour, XRD indicated the
solid to be composed of whitlockite as the primary phase along with
hydroxyapatite as the secondary phase. XRD results indicate that
the relative ratio of the two calcium phosphate phases was
dependent on the duration of the heat treatment, but no attempts
were made to quantify the dependence.
9 Heated to 500.degree. C., 1 hour (Major) Whitlockite
[b-Ca.sub.3(PO.sub.4).sub.2] (minor) Ca.sub.5(PO.sub.4).sub.3-x(C-
O.sub.3).sub.x(OH)
Example 10
Low Temperature Aluminum Phosphate Powders
[0165] An aqueous solution of 10.82 g 50 wt % H.sub.3PO.sub.2 was
combined with 2.00 g distilled water to form a clear, colorless
solution contained in a 250 ml Pyrex beaker. To this solution was
added 30.78 g aluminum nitrate nonahydrate salt,
Al(NO.sub.3).sub.3.9H.sub.2O (ACS reagent, Alfa/Aesar reagent
#36291, CAS #7784-27-2), equivalent to 7.19 wt % Al. The molar
ratio of Al/phosphate in this mixture was 1/1 and the equivalent
solids level [as AlPO.sub.4] was 22.9 wt %. Endothermic dissolution
of the aluminum nitrate nonahydrate proceeded giving a homogeneous
solution once the sample warmed to room temperature. Further
warming of this solution to >25.degree. C. on a hotplate
initiated a reaction in which the solution vigorously evolved
red-brown acrid fumes of NO.sub.x(g). Reaction continued for
approximately 15 minutes during which the solution viscosity
increased considerably prior to formation of a white solid.
[0166] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air at 500.degree. C.C for 0.5 hour, XRD analysis indicated the
solid to be composed of AlPO.sub.4 (PDF 11-0500) plus some
amorphous material, suggesting that the heat treatment was not
sufficient to induce complete sample crystallization.
Example 11
Low Temperature Calcium Phosphate Powders
[0167] An aqueous solution of 8.06 g 50 wt % H.sub.3PO.sub.2
reagent was combined with 6.00 g distilled water to form a clear,
colorless solution in a 250 ml Pyrex beaker on a hotplate/stirrer.
To this solution was added 19.23 g Ca(NO.sub.3).sub.2.4H.sub.2O.
The molar ratio of Ca/phosphate in this sample was 4/3 and the
equivalent solids [as octacalcium phosphate,
Ca.sub.8H.sub.2(PO.sub.4).sub.6-5H.sub.2O ] was 30.0 wt %.
Endothermic dissolution of the calcium nitrate tetrahydrate
proceeded under ambient conditions, eventually forming a
homogeneous solution once the sample warmed to room temperature.
Warming of the solution above 25.degree. C. initiated a vigorous
exothermic reaction as described in Example 1. After approximately
three minutes, the reaction was essentially complete leaving a
moist, white, pasty solid.
[0168] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air at 500.degree. C. for 0.5 hour, XRD indicated the solid to be
composed of whitlockite as the primary phase along with
hydroxyapatite as the secondary phase. There was no evidence for
the formation of octacalcium phosphate (OCP), despite the initial
sample stoichiometry. This result suggests that (a) alternate heat
treatments are necessary to crystallize OCP and/or (b) excess Ca is
present in the intermediate powder.
10 Heated to 500.degree. C., 0.5 hour (Major) Whitlockite
[b-Ca.sub.3(PO.sub.4).sub.2] (minor) HAp
Ca.sub.5(PO.sub.4).sub.3(OH)
Example 12
Low Temperature Calcium Phosphate Powders
[0169] Example 11 was repeated except that no distilled water was
used in preparation of the reaction mixture. Warming of the
homogeneous solution above 25.degree. C. initiated an exothermic
reaction as described in Example 11. After approximately three
minutes, the reaction was essentially complete leaving a moist,
pasty, white solid.
[0170] Heat treatment and X-ray diffraction of this solid were
conducted as described in Example 1. Following heat treatment in
air at 500.degree. C. for 0.5 hour, XRD indicated the solid to be
composed of calcium pyrophosphate (Ca.sub.2P.sub.2O.sub.7).
[0171] Heated to 500.degree. C., 0.5 hour (Major)
Ca.sub.2P.sub.2O.sub.7
Example 13
Low Temperature Hydrothermal (HYPR) Calcium Phosphates
[0172] An aqueous solution of 50 wt % calcium nitrate tetrahydrate,
Ca(NO.sub.3).sub.2-4H.sub.2O (ACS reagent, Aldrich Chemical Co.,
Inc. #23,712-4, CAS #13477-34-4) was prepared by dissolving 250.0 g
of the salt in 250.0 g distilled water. This solution was
equivalent to 8.49 wt % Ca. A total of 47.0 g of this solution was
added, with rapid agitation, to an aqueous solution of 50 wt %
sodium hypophosphite monohydrate, NaH.sub.2PO.sub.2-H.sub.2O
(Alfa/Aesar reagent #14104, CAS #10039-56-2) also prepared by
dissolving 250.0 g of the salt in 250.0 g distilled water. The
sodium hypophosphite solution was equivalent to 44.80 wt %
[PO.sub.4].sup.-3. The clear, colorless solution of calcium nitrate
and sodium hypophosphite was then diluted with 40.3 g distilled
water. The molar ratio of Ca/phosphate in this mixture was 5/3, and
the equivalent solids level [as Ca5(PO.sub.4).sub.3(OH)
(hydroxyapatite)] was 10.0 wt %. The sample was hydrothermally
treated using a 300 cc volume stirred high pressure bench reactor
(Model no. 4561 Mini Reactor, Parr Instrument Co., Moline, Ill.
61265) equipped with a temperature controller/digital tachometer
unit (Model no. 4842, Parr Instrument Co.) and dial pressure gauge.
All wetted parts of the reactor were fabricated from type 316
stainless steel. Ordinarily, type 316SS is not the material of
choice for inorganic acid systems such as the solution precursors
used in this invention, since phosphoric acid can attack stainless
steel at elevated temperatures and pressures. However, in the
practice of this invention, direct contact (i.e. wetting) of the
reactor surfaces was avoided through the use of a Pyrex glass
liner. Only the stirrer and thermocouple sheath were immersed in
the reactant solutions and no corrosion was observed. In addition,
it is assumed that the high nitrate ion concentration in the
reactant mixture provided a passivating environment for the type
316SS.
[0173] One hundred grams (approximately 100 ml) of the calcium
nitrate-sodium hypophosphite solution was placed in the Pyrex liner
of the reactor and the intervening space between the glass liner
and the reactor vessel was filled with distilled water to the level
of the sample. This ensured maximum heat transfer to the sample
since the reactor was externally heated by an electric mantle. The
approx. 100 ml sample volume left sufficient head space in the
reactor to accommodate solution expansion at elevated temperatures.
The reactor was sealed by compression of a Teflon gasket. Heating
of the reactor was performed at the maximum rate of the controller
to a set point of 202.degree. C. with constant stirring (500
r.p.m.). The heating profile, as monitored by a thermocouple
immersed in the reactant mixture, was as follows:
11 REACTOR THERMAL PROFILE Time 0 5 10 15 20 25 30 35 36 (min)
Temp. 22 49 103 122 145 155 179 197 200 (.degree. C.) (+/-2.degree.
C.) (hold) Pressure -- -- -- -- -- -- 160 210 220 (psi)
[0174] After holding at 200+/-3.degree. C. for 12 minutes, the
temperature rapidly increased to 216.degree. C. with a resultant
increase in reactor pressure to approximately 330 psi. This
exothermic event quickly subsided as evidenced by the rapid drop in
reactor temperature to 208.degree. C. within two minutes as the
Parr reactor approached thermal equilibrium via a near-adiabatic
process. After 15 minutes at 200.degree. C., the reactor was
removed from the heating mantle, quenched in a cold water bath, and
opened after the head space was vented to ambient pressure.
[0175] A white precipitate was present in the glass liner. The
solid was collected by vacuum filtration on a 0.45 micron membrane
filter (Millipore, Inc., Bedford, MA, 01730), washed several times
with distilled water, and dried at approximately 55.degree. C. in a
forced convection oven. X-ray diffraction of this solid was
conducted as described in Example 1.
[0176] X-Ray diffraction results indicate a unique, unidentifiable
diffraction pattern.
Example 14
Low Temperature Hydrothermal (HYPR) Calcium Phosphate Powders
[0177] Example 13 was repeated except that 40.3 g of 1.0 M NaOH
solution was added with rapid stirring to the homogeneous solution
of calcium nitrate and sodium hypophosphite instead of the
distilled water. This base addition resulted in the formation of a
milk white dispersion, presumably due to precipitation of
Ca(OH).sub.2.
[0178] The sample was hydrothermally processed as described in
Example 13 with the temperature set point at 207.degree. C. The
temperature ramp to 160.degree. C. (25 minutes) was as indicated
for Example 13. At 30 minutes into the run, an exotherm occurred
causing the temperature of the reaction mixture to rise to a
maximum of 221.degree. C. within five minutes with a corresponding
pressure increase to 370 psi. At 38 minutes into the experiment,
the reactor was quenched to room temperature.
[0179] The reaction product consisted of a small amount of white
precipitate. The material was collected as described in Example 13.
X-ray diffraction of the dried sample was conducted as described in
Example 1. XRD results indicated the solid to be comprised of the
same unidentifiable pattern (crystal phase) found in Example 13 and
minor amounts of HAp-[Ca.sub.5(PO.sub.4).sub.3(OH)].
Example 15
Low Temperature Hydrothermal (HYPR) Calcium Phosphate Powders
[0180] A total of 47.0 g of a 50 wt % aqueous solution of calcium
nitrate tetrahydrate was diluted with 53.0 g distilled water. Then,
6.00 g calcium hypophosphite salt, Ca(H.sub.2PO.sub.2).sub.2
(Alfa/Aesar reagent #56168, CAS #7789-79-9), equivalent to 23.57 wt
% Ca and 111.7 wt % [P.sub.4].sup.-3 was slurried into the
Ca(NO.sub.3).sub.2 solution using rapid agitation. An unknown
amount of the calcium hypophosphite remained undissolved in the
room temperature sample. The solubility behavior of
Ca(H.sub.2PO.sub.2).sub.2 in the Ca(NO.sub.3).sub.2 solution at
elevated temperatures is unknown. The molar ratio of Ca/phosphate
in this system was 1.91.
[0181] This sample was hydrothermally processed as described in
Example 13 with the temperature set point at 212.degree. C. The
temperature ramp to 200.degree. C. was as indicated for Example 13.
At 39 minutes into the run, an exotherm occurred causing the
temperature of the reaction mixture to rise to a maximum of
252.degree. C. within three minutes with a corresponding pressure
increase to 640 psi. At 44 minutes into the experiment, the reactor
was quenched to room temperature.
[0182] The reaction product appeared as a voluminous white
precipitate plus some suspended solids. The material was collected
as described in Example 13. X-ray diffraction of the dried solid
was conducted as described in Example 1. XRD showed the major peak
at position 30.2.degree. (2-theta) which indicated the solid to be
monetite, CaHPO.sub.4. The unique crystal morphology is depicted in
the scanning electron micrograph representation in FIG. 2.
[0183] Mixtures of the above described RPR and HYPR powders are
useful in the formation of self-setting calcium phosphate cements
for the repair of dental and orthopaedic defects. The addition of
specific components and solubilizing liquids can also be added to
form the precursor bone mineral constructs of this invention.
Example 16
Cement Compositions
[0184] Approximately 1.4 g of an alkaline solution (7 molar) formed
using NaOH and distilled water, was mixed with 1.1 g of HYPR
monetite [Example 15] and 1.1 g of RPR .beta.-TCP-HAp(CO.sub.3)
[Example 3] in a glass mortar and pestle for .about.45 seconds.
After mixing, a smooth paste was formed, which was scooped into a 3
ml polypropylene syringe and sealed for 20 minutes without being
disturbed. Room temperature setting was observed after 20 minutes,
which was indicated by the use of a 454 gram Gilmore needle. The
hardened cement analyzed by X-ray diffraction showed peaks which
revealed a conversion to primarily type-B, carbonated apatite which
is the desired bone mineral precursor phase:
12 Cement XRD revealed (Major) Ca.sub.5(PO.sub.4).sub.3--
x(CO.sub.3).sub.x(OH) (minor) Whitlockite [b-Ca.sub.3(PO.sub.4).s-
ub.2]
Example 17
Cement Compositions
[0185] A stock solution was formed with the approximately 7 M NaOH
solution used in Example 1 and 1.0% polyacrylic acid (PAA). PAA is
used as a chelating setting additive and wetting agent. The above
solution was used with several powder combinations to form setting
cements. A 50/50 powder mix of HYPR monetite [Example 15] and RPR
.beta.-TCP-HAp(CO.sub.3) [Example 3], approximately 0.7 g, was
mixed with a glass spatula on a glass plate with 0.39 g of the 1%
PAA-NaOH solution (powder to liquid ratio=1.73). The cement was
extruded through a 3 ml syringe and was set after being left
undisturbed for 20 minutes at room temperature (23.degree. C.).
Examples 18-34
[0186]
13 Set Time Powder/ (min.) Powder/ Gilmore Needle Liquid ratio (454
grams) Example Powder Liquid (Consistency) # = (1200 grams) 18 HYPR
monetite + 7M NaOH 1/1/1.2 <20 min(#) RPR (Ex. 1) 500.degree. C.
Alkaline Sol'n (slightly wet paste) 19 HYPR monetite 7M NaOH
1/1/1.2 <20 min (#) (Ex. 15) + Alkaline Sol'n (wet paste) RPR
(Ex. 1) 700.degree. C. 20 HYPR monetite 7M NaOH 1/1/1 15-18 min
(Ex. 15) + Alkaline Sol'n (sl. wet paste) -50 .mu.m 45S5.sup.#
glass 21 RPR (Ex. 1) 500.degree. C. 7M NaOH 1.5/1 >40 min `neat`
Alkaline Sol'n (wet paste) 22 RPR (Ex. 1) 300.degree. C. + 7M NaOH
1.7/1 40 min RPR (Ex. 9) Alkaline Sol'n (sl. wet paste) 500.degree.
C. 23 HYPR monetite 7M NaOH 1/1/1.4 No Set up to (Ex. 15) +
Alkaline Sol'n (v. gritty, wet) 24 hrs. Commercial .beta.- TCP 24
HYPR monetite 7M NaOH 1/1/1.4 20 min (#) (Ex. 15) + Alkaline Sol'n
(slightly wet RPR (Ex. 2) 500.degree. C. paste) 25 HYPR monetite 7M
NaOH 1/1/1 <30 min (Ex. 15) + Alk. Sol'n + (claylike sl. set RPR
(Ex. 2) 500.degree. C. 20% PAA paste) 26 HYPR monetite 7M NaOH
1/1/1 35 min (Ex. 15) + Alk. Sol'n + (claylike RPR (Ex. 2)
500.degree. C. 5% PAA paste) 27 HYPR monetite 7M NaOH 1/1/1.2 12-15
min (Ex. 15) + Alk. Sol'n + (slightly dry RPR 1% PAA paste) (Ex.
11) 500.degree. C. 28 HYPR monetite 10 wt % 1/1/1.2 1 hr 15 min
(Ex. 15) + Ca(H.sub.2PO.sub.2).sub.2 (very wet RPR (Ex. 1)
500.degree. C. (aq) paste) 29 RPR 10 wt % 1.7/1 45 min (Ex. 11)
500.degree. C. Ca(H.sub.2PO.sub.2).sub.2 (very wet paste) `neat`
(aq) 30 RPR 10 wt % 2.5/1 20 min (Ex. 11) 500.degree. C.
Ca(H.sub.2PO.sub.2).sub.2 (sl. dry `neat` (aq) paste/putty) 31 RPR
10 wt % 2.25/1 15 min (Ex. 11) 500.degree. C.
Ca(H.sub.2PO.sub.2).sub.2 + (very good `neat` 1 wt % paste/putty)
H.sub.2PO.sub.2 (aq) 32 HYPR monetite 3.5M NaOH 1/1/1 35 min. (Ex.
15) + Alk. Sol'n. (good *12 min. RPR paste/putty) (Ex. 11)
500.degree. C. 33 HYPR monetite 3.5M NaOH 1/3/2 38 min. (Ex. 15) +
Alk. Sol'n. (paste/putty) *15 min. RPR (Ex. 11) 500.degree. C. 34
HYPR monetite Saline, EDTA 1/1/1 43 min. (Ex. 15) + buffered (good
*20 min. RPR paste/putty) (Ex. 11) 500.degree. C. *Set Time at
37.degree. C., 98% Relative Humidity. HYPR monetite `
HYdrothermally PRocessed monetite (CaHPO.sub.4). RPR =
Reduction-oxidation Precipitation Reaction. #45S5 glass = {24.5%
CaO-24.5% Na.sub.2O-6% P.sub.2O.sub.5-45% SiO.sub.2 (wt %)}. PAA =
Polyacrylic acid. Commercial .beta.-TCP from Clarkson
Chromatography Products, Inc. (S. Williamsport, PA)
Example 35
Low Temperature Neodymium Phosphate Powders
[0187] An aqueous solution of 11.04 g of 50 wt. % H.sub.3PO.sub.2
was diluted with 5.00 g distilled water to form a clear, colorless
solution contained in a 250 ml fluoropolymer resin beaker on a
hotplate/magnetic stirrer. Added to this solution was 36.66 g
neodymium nitrate hexahydrate salt, Nd(NO.sub.3).sub.3-6H.sub.2O
(AlfalAesar reagent #12912, CAS # 16454-60-7), equivalent to 32.90
wt % Nd. The molar ratio of the Nd/P in this mixture was 1/1 and
the equivalent solids level (as NdPO.sub.4) was 38.0 wt. %.
Endothermic dissolution of the neodymium nitrate hexahydrate salt
proceeded with gradual warming of the reaction mixture, eventually
forming a clear, homogeneous lavender solution at room temperature.
Heating of this solution with constant agitation to approximately
70.degree. C. initiated a vigorous endothermic reaction which
resulted in the evolution of NO.sub.x(g), rapid temperature
increase of the sample to approximately 100.degree. C. , and
finally, formation of a pasty lavender mass. Heat treatment of the
pasty solid and subsequent X-ray diffraction analysis of the fired
solid were conducted as described in Example 1. Results of the
analysis are as follows:
14 Heated to 500.degree. C., 45 minutes (Major) Neodymium phosphate
hydrate [NdPO.sub.4-0.5H.sub.2O] (PDF 34-0535) Heated to
700.degree. C., 45 minutes (Major) Monazite-Nd [NdPO.sub.4] (PDF
46-1328)
Example 36
Low Temperature Cerium Phosphate Powders
[0188] An aqueous solution of 11.23 g of 50 wt. % H.sub.3PO.sub.2
was diluted with 5.00 g distilled water to form a clear, colorless
solution contained in a 250 ml fluoropolymer resin beaker on a
hotplate/magnetic stirrer. Added to this solution was 36.94 g
cerium nitrate hexahydrate salt, Ce(NO.sub.3).sub.3-6H.sub.2O
(Johnson-Matthey reagent #11329-36), equivalent to 32.27 wt % Ce.
The molar ratio of the Ce/P in this mixture was 1/1 and the
equivalent solids level (as CePO.sub.4) was 37.6 wt %. Endothermic
dissolution of the neodymium nitrate hexahydrate salt proceeded
with gradual warming of the reaction mixture, eventually forming a
clear, homogeneous colorless solution at room temperature. Heating
of this solution with constant agitation to approximately
65.degree. C. initiated a vigorous endothermic reaction which
resulted in the evolution of NO.sub.x(g), rapid temperature
increase of the sample to approximately >100.degree. C., and
finally, formation of a pasty light grey mass. Heat treatment of
the pasty solid and subsequent X-ray diffraction analysis of the
fired solid were conducted as described in Example 1. Results of
the XRD analysis are as follows:
[0189] Heated to 700.degree. C., 45 minutes (Major) Monazite-Ce
[CePO.sub.4] (PDF 32-0199)
Example 37
Low Temperature Yttrium Phosphate Powders
[0190] An aqueous solution of 14.36 g of 50 wt. % H.sub.3PO.sub.2
was diluted with 5.00 g distilled water to form a clear, colorless
solution contained in a 250 ml fluoropolymer resin beaker on a
hotplate/magnetic stirrer. Added to this solution was 41.66 g
yttrium nitrate hexahydrate salt, Y(NO.sub.3).sub.3-6H.sub.2O
(Alfa/Aesar reagent #12898, CAS #13494-98-9), equivalent to 23.21
wt % Y. The molar ratio of the Y/P in this mixture was 1/1 and the
equivalent solids level (as YPO.sub.4) was 32.8 wt %. Endothermic
dissolution of the yttrium nitrate hexahydrate salt proceeded with
gradual warming of the reaction mixture, eventually forming a
clear, homogeneous colorless solution at room temperature. Heating
of this solution with constant agitation to approximately
75.degree. C. initiated a vigorous endothermic reaction which
resulted in the evolution of NO.sub.x(g), rapid temperature
increase of the sample to approximately >100.degree. C. , and
finally, formation of a pasty white mass. Heat treatment of the
pasty solid and subsequent X-ray diffraction analysis of the fired
solid were conducted as described in Example 1. Results of the XRD
analysis are as follows: Heated to 700.degree. C., 45 minutes
(Major) Xenotime [YPO.sub.4] (PDF 11-0254)
Example 38
Broad Applicabililty
[0191] A wide variety of minerals can be made in accordance with
the present invention. In the following two tables, oxidizing and
reducing agents are listed. Any of the listed oxidants can be
reacted with any of the listed reducing agents and, indeed, blends
of each may be employed. Appropriate stoichiometry will be employed
such that the aforementioned reaction is caused to proceed. Also
specified are possible additives and fillers to the reactions. The
expected products are given as are some of the expected fields of
application for the products. All of the following are expected
generally to follow the methodology of some or all of the foregoing
Examples.
15 Oxidizing Agents Reducing Agents Additives Product(s) Compounds
of the form Oxoacids of Group 5B, 6B, Al.sub.2O.sub.3, ZrO.sub.2,
TiO.sub.2, SiO.sub.2, Ca(OH).sub.2, XY(PO.sub.4) , XY(SO.sub.4),
XNO.sub.3, where X = and 7B, (where 5B includes N, DCPD, DCPA, HAp,
TCP, TTCP, XY(PO.sub.4)(SO.sub.4), H, Li, Na, K, Rb, Cs, P, and As;
6B includes S, Se, MCMP, ZrSiO.sub.4, W-metal, Fe metal, Ti
WXYZ(PO.sub.4)(SO.sub.4)(CO.sub.3), Cu, Ag, and Hg. and Te; 7B
includes Cl, Br, metal, Carbon black, C-fiber or flake,
WXYZ(PO.sub.4)(SO.sub.4)(CO.sub.3)(F, Cl, Compounds of the form and
I). CaF.sub.2, NaF, carbides, nitrides, glass Br, I),
WXYZ(PO.sub.4)(SO.sub.4) X(NO.sub.3).sub.2, where X = Be,
Phosphorous oxoacid fibers, glass particulate, glass-ceramics,
(CO.sub.3)(F, Cl, Br, I)(OCl, OF, Mg, Ca, Sr. Ba, Cr, Mn,
compounds: alumina fibers, ceramic fibers, OBr, OI), in the form of
fiber, Fe, Co, Ni, Cu, Zn, Rh, Hypophosphite (H.sub.3PO.sub.2);
bioactive ceramic fibers and flake, whisker, granule, Pd, Cd, Sn,
Hg, and Pb Hypophosphoric acid particulates, polyacrylic acid,
polyvinyl coatings, agglomerates and (H.sub.4P.sub.2O.sub.6);
alcohol, polymethyl-methacrylate, fine powders. Isohypophosphoric
acid polycarbonate, and other stable (H.sub.4P.sub.2O.sub.6);
polymeric compounds. Phosphonic acid or Acetates, formates,
lactates, simple phosphorus acid (H.sub.3PO.sub.3); carboxylates,
and simple sugars. Diphosphonic acid (H.sub.4P.sub.2O.sub.5);
Phosphinic acid or hypophosphorous acid Compounds of the form
Sulfur oxoacid compounds: X(NO.sub.3).sub.3 or XO(NO.sub.3),
Thiosulfuric acid (H.sub.2S.sub.2O.sub.3); where X = Al, Cr, Mn,
Dithionic acid (H.sub.2S.sub.2O.sub.6); Fe, Co, Ni, Ga, As, Y,
Polythionic acid (H.sub.2S.sub.n+2O.sub.6); Nb, Rh, In, La, Ti, Bi,
Sulfurous acid (H.sub.2SO.sub.3); Ac, Ce, Pr, Nd, Steven
Disulfurous acid (H.sub.2S.sub.2O.sub.5); Meyer, Eu, Gd, Tb, Dy,
Dithionous acid (H.sub.2S.sub.2O.sub.4). Ho, Er, Tm, Yb, Lu, U, and
Pu Compounds of the form X(NO.sub.3).sub.4 or XO(NO.sub.3).sub.2,
where X = Mn, Sn, Pd, Zr, Pb, Ce, Pr, Tb, Th, Pa, U and Pu. Halogen
oxoacids:
[0192] The minerals prepared above may be used in a wide variety of
applications. Examples of these applications may include, but are
not limited to, use as pigments, phosphors, fluorescing agents,
paint additives, synthetic gems, chromatography media, gas scrubber
media, filtration media, bioseparation media, zeolites, catalysts,
catalytic supports, ceramics, glasses, glass-ceramics, cements,
electronic ceramics, piezoelectric ceramics, bioceramics, roofing
granules, protective coatings, barnacle retardant coating, waste
solidification, nuclear waste solidification, abrasives, polishing
agents, polishing pastes, radiopharmaceuticals, medical imaging and
diagnostics agents, drug delivery, excipients, tabletting
excipients, bioactive dental and orthopaedic materials and
bioactive coatings, composite fillers, composite additives,
viscosity adjustment additives, paper finishing additives, optical
coatings, glass coatings, optical filters, fertilizers, soil
nutrient(s) additives.
Example 39
Porous Shaped Bodies of Calcium Phosphates
[0193] An aqueous solution of 17.02 g 50 wt % hypophosphorous acid,
H.sub.3PO.sub.2 (Alfa/Aesar reagent #14142, CAS #6303-21-5),
equivalent to 71.95 wt % [PO.sub.4].sup.-3 was combined with 5.00 g
deionized water to form a clear, colorless solution contained in a
250 ml Pyrex beaker. To this solution was added 45.70 g calcium
nitrate tetrahydrate salt, Ca(NO.sub.3).sub.2.4H.sub.2O (ACS
reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4),
equivalent to 16.97 wt % Ca. The molar ratio of
[Ca].sup.2+/[PO.sub.4].sup.-3 in this mixture was 3/2 and the
equivalent solids level [as Ca.sub.3(PO.sub.4).sub.2] was 29.53 wt
%. Endothermic dissolution of the calcium nitrate tetrahydrate
proceeded under ambient temperature conditions, eventually forming
a homogeneous solution. The viscosity of this solution was
water-like, despite the high salt concentration.
[0194] A piece of damp (as removed from the packaging) cellulose
sponge (O-Cel-O.sub.TM, 3M Home and Commercial Care Division, P.O.
Box 33068, St. Paul. Minn. 55133), trimmed to a block approximately
1.5".times.1.5".times.2.0", was immersed in the calcium
nitrate+hypophosphorous acid solution and kneaded (alternately
compressed and decompressed) to fully imbibe the reactant solution
into the sponge. The approximately 4.5 cubic inch sponge block
(approximately 3.5 g), thoroughly saturated with reactant solution
(liquid uptake approximately 7 to 8 times the virgin sponge
weight), was placed on a platinum plate in a laboratory furnace
(Vulcan model 3-550, NEYTECH, Inc., 1280 Blue Hills Ave.,
Bloomfield, Conn. 06002) that was preheated to 500.degree. C. After
several seconds, a reaction commenced at the surface of the sponge
with the evolution of red-brown fumes characteristic of
NO.sub.x(g). As the reaction proceeded from the surface to the
interior of the sponge block, NO.sub.x(g) evolution continued and
some reactant liquid exuded from the sponge and accumulated at the
bottom of the Pt plate as a crusty white mass of solid. The
cellulose sponge itself was consumed as the reaction progressed and
the reactant mass attained the oven temperature. After thermal
treatment at 500.degree. C. for 45 minutes, the sample was removed
from the lab furnace. The sample had been converted to an inorganic
replica of the original organic sponge structure. The vestigial
structure represented a positive version of the original sponge
structure with faithful replication of the cellular elements,
porosity, and macrostructure. The vestigial mass was mottled gray
suggesting the presence of some residual carbon in the structure
due to incomplete burnout of the combustion products from the
cellulose sponge matrix. The vestigial mass was fragile with very
low apparent density, but it was robust enough to be handled as a
coherent block of highly porous solid once it was removed from the
exudate material.
[0195] An X-ray diffraction (XRD) pattern was obtained from a
packed powder sample of the inorganic sponge material pulverized in
a mortar and pestle. The pattern was obtained using a Rigaku
MiniFlex instrument (Rigaku/USA, Inc., Northwoods Business Park,
199 Rosewood Dr., Danvers, Mass. 01923) running JADE pattern
processing software (Materials Data, Inc., P.O. Box 791, Livermore,
Calif. 94551) using a 2 degree/minute scan rate over the 2 theta
angular range from 15-50.degree.. The XRD pattern for this material
is shown in FIG. 11. Peak analysis indicated the solid to consist
of whitlockite Ca.sub.3(PO.sub.4).sub.2 (PDF 09-0169) and
hydroxyapatite Ca.sub.5(PO.sub.4).sub.3(OH) (PDF 09-0432).
[0196] A sample of the O-Cel-O.TM. cellulose sponge was prepared
for scanning electron microscopy by sputter coating with Pt using a
Hummer 6.2 Sputtering System (Anatech, Inc., 6621-F Electronic
Drive, Springfield, Va. 22151). SEM examination was performed using
a JEOL model JSM-840A microscope (JEOL USA, Inc., 11 Dearborn Road,
P.O. Box 6043, Peabody, Mass. 01961). FIG. 12 shows a SEM image of
the virgin cellulose sponge. FIG. 13 shows a SEM image of the
calcium phosphate material prepared from the cellulose sponge.
Example 40
Transformed Shaped Bodies of Calcium Phosphate
[0197] The material from Example 39 was fired under a variety of
conditions in order to (1) eliminate residual carbon from the
structure and (2) attempt to promote sintering reactions in order
to strengthen the inorganic sponge matrix. The samples were fired
on Pt plates in a Lindberg model 51333 box firnace (Lindberg/Blue
M, Inc., 304 Hart St., Watertown, Wis. 53094) equipped with a
Lindberg series 59000 control console. The following table
summarizes these results:
16 Temp./time Observations XRD 900.degree. C. 15 minutes Snow white
mass 1000.degree. C. 1 hour Snow white mass 1100.degree. C. 1 hour
Snow white mass 1100.degree. C. 13 hours Snow white mass
Whitlockite (FIG. 14) 1200.degree. C. 13 hours Snow white mass
1350.degree. C. 1 hour Snow white mass Whitlockite (FIG. 15)
[0198] A subjective assessment of the strength of these heat
treated specimens showed no apparent changes. There was no
indication that sintering occurred even at temperatures up to
1350.degree. C.
Example 41
Shaped Bodies
[0199] A solution was prepared as described in Example 39 using
9.70 g 50wt % H.sub.3PO.sub.2, no deionized water, and 17.38 g
Ca(NO.sub.3).sub.2.4H.sub.2O to obtain a molar ratio of
[Ca].sup.2+/[PO.sub.4].sup.-3 of 1.0 and an equivalent solids level
[as CaHPO.sub.4] of 36.92 wt %. A small block of damp O-Cel-O.TM.
sponge (as removed from the packaging) was fully imbibed with the
reactant solution, set in a porcelain crucible, and placed into a
Vulcan lab oven preheated to 500.degree. C. After 1 hour at
500.degree. C., the mottled gray sample was refired at 800.degree.
C. (Vulcan furnace) for 15 minutes. The final inorganic sponge
sample was completely white indicating complete carbon burnout. An
XRD pattern (FIG. 16) was obtained from a packed powder sample
prepared as described in Example 39. Peak analysis indicated the
solid to consist of calcium pyrophosphate, Ca.sub.2P.sub.2O.sub.7
(PDF 33-0297).
Example 42
Shaped Bodies of Zinc Phosphate
[0200] An aqueous solution of 13.67 g 50 wt % H.sub.3PO.sub.2 was
combined with 5.00 g deionized water to form a clear, colorless
solution contained in a 250 ml Pyrex beaker. To this solution was
added 46.23 g zinc nitrate hexahydrate salt,
Zn(NO.sub.3).sub.2.6H.sub.2O (Aldrich Chemical Co., Inc. #22,873-7,
CAS #10196-18-6), equivalent to 21.97 wt. % Zn. The molar ratio of
[Zn].sup.2+/[PO.sub.4].sup.-3 in this mixture was 3/2 and the
equivalent solids level [as Zn.sub.3(PO.sub.4).sub.2] was 27.5 wt.
%.
[0201] Endothermic dissolution of the zinc nitrate hexahydrate
proceeded under ambient temperature conditions, eventually forming
a homogeneous solution. A block of O-Cel-O.TM. sponge was fully
imbibed with this reactant solution as described in Example 39. The
sample was first fired at 500.degree. C. for 1 hour and then at
800.degree. C. for 15 minutes. The inorganic sponge sample was
light gray in color (due to residual carbon) and it was robust
enough to be handled as a coherent block of low density, highly
porous material. An XRD pattern (FIG. 17) was obtained from a
packed powder sample prepared as described in Example 39. Peak
analysis indicated the solid to consist of zinc phosphate,
Zn.sub.3(PO.sub.4).sub.2 (PDF 30-1490).
Example 43
Neodymium Phosphate Bodies
[0202] An aqueous solution of 11.04 g 50 wt % H.sub.3PO.sub.2 was
combined with 5.00 g deionized water to form a clear, colorless
solution contained in a 250 ml Pyrex beaker. To this solution was
added 36.64 g neodymium nitrate hexahydrate salt,
Nd(NO.sub.3).sub.3.6H.sub.2O (Alfa/Aesar reagent #12912, CAS
#16454-60-7), equivalent to 32.90 wt % Nd. Endothermic dissolution
of the neodymium nitrate hexahydrate proceeded under ambient
temperature conditions, eventually forming a pale lavender
homogeneous solution. A block of O-Cel-O.TM. sponge was fully
imbibed with this reactant solution as described in Example 39. The
sample was first fired at 500.degree. C. for 1 hour and then at
800.degree. C. for 15 minutes. The inorganic sponge sample was pale
lavender in color at the outside of the inorganic sponge mass and
light gray in the interior (due to residual carbon). The inorganic
sponge mass was very fragile, but it was robust enough to be
handled as a coherent block of low density, highly porous material.
An XRD pattern (FIG. 18) was obtained from a packed powder sample
prepared as described in Example 39. Peak analysis indicated the
solid to consist of neodymium phosphate, NdPO.sub.4 (PDF
25-1065).
Example 44
Aluminium Phosphate Bodies
[0203] An aqueous solution of 21.65 g 50 wt % H.sub.3PO.sub.2 was
combined with 5.00 g deionized water to form a clear, colorless
solution contained in a 250 ml Pyrex beaker. To this solution was
added 61.56 g aluminum nitrate nonahydrate salt,
Al(NO.sub.3).sub.3.9H.sub.2O (Alfa/Aesar reagent #36291, CAS
#7784-27-2), equivalent to 7.19 wt. % Al. Endothermic dissolution
of the aluminum nitrate hexahydrate proceeded under ambient
temperature conditions, eventually forming a homogeneous solution.
A block of O-Cel-O.TM. sponge was fully imbibed with this reactant
solution as described in Example 39. The sample was first fired at
500.degree. C. for 1 hour and then at 800.degree. C. for 15
minutes. The inorganic sponge sample was white at the outside of
the inorganic sponge mass and light gray in the interior (due to
residual carbon). The inorganic sponge mass could be handled as a
coherent block of low density, highly porous material. An XRD
pattern (FIG. 19) was obtained from a packed powder sample prepared
as described in Example 39. Peak analysis indicated the solid to
consist of aluminum phosphate, AlPO.sub.4 (PDF 11-0500).
Example 45
Modified Porous Structures
[0204] A piece of the inorganic sponge material from Example 39 was
immersed in molten paraffin wax (CAS #8002-74-2) (Northland Canning
Wax, Conros Corp., Detroit, Mich. 48209) maintained at
>80.degree. C. so as to imbibe the porous structure. The
inorganic sponge, wetted with molten wax, was removed from the
molten wax and allowed to cool at room temperature. The wax
solidified on cooling and imparted additional strength and improved
handling properties to the inorganic sponge material such that the
paraffin wax-treated material could be cut and shaped with a knife.
Most of the formerly open porosity of the inorganic sponge material
was filled with solidified paraffm wax.
Example 46
Gelatin Modification
[0205] A piece of the inorganic sponge material from Example 39 was
immersed in a solution prepared by dissolving 7.1 g food-grade
gelatin (CAS # 9000-70-0) (Knox Unflavored Gelatin, Nabisco Inc.,
East Hanover, N.J. 07936) in 100.0 g deionized water at
approximately 90.degree. C. The inorganic sponge material readily
imbibed the warm gelatin solution and, after several minutes, the
largely intact piece of inorganic sponge material was carefully
removed from the solution and allowed to cool and dry overnight at
room temperature. The gelatin solution gelled on cooling (bloom
strength unknown) and imparted additional strength and improved
handling properties to the inorganic sponge material. Although no
pH or electrolyte/nonelectrolyte concentration adjustments were
made to the system described in this example, it is anticipated
that such adjustments away from the isoelectric point of the
gelatin would impart additional rigidity to the gelatin gel and,
thereby, to the gelatin-treated inorganic sponge material.
Significant additional strength and improved handling properties
were noted in the gelatin-treated inorganic sponge material after
the gelatin was allowed to thoroughly dry for several days at room
temperature. Some shrinkage of the gelatin-treated inorganic sponge
materials was noted on drying. The shrinkage was nonuniform with
the greatest contraction noted near the center of the body. This
central region was, of course, the last area to dry and, as such,
was surrounded by hardened inorganic sponge material which could
not readily conform to the contraction of the core as it
dehydrated. The material exhibited considerable improvement in
compression strength and a dramatically reduced tendency to shed
particulate debris when cut with a knife or fine-toothed saw. It is
presumed that the film-forming tendency of the gelatin on drying
induced compressive forces on the internal cellular elements of the
inorganic sponge material, thereby strengthening the overall
structure.
[0206] Cylindrical plugs could be cored from pieces of the air
dried gelatin-treated inorganic sponge material using hollow punch
tools ranging from 1/2 inch down to 1/8 inch in diameter.
[0207] FIG. 20 is a SEM of the air-dried gelatin treated inorganic
sponge, which was prepared as described in Example 39. A comparison
of this SEM with that of the initial cellulose sponge material
(FIG. 12) shows how faithfully the sponge micro- and macrostructure
has been replicated in the inorganic sponge material. FIG. 21 is a
SEM of sheep trabecular bone. The highly porous macrostructure of
sheep trabecular bone is representative of the anatomical structure
of cancellous bone of higher mammals, including humans. The sample
of sheep trabecular bone was prepared for SEM analysis by sputter
coating (as described in Example 39) a cross-sectional cut from a
desiccated sheep humerus. FIG. 22 is a higher magnification SEM of
the air-dried gelatin treated inorganic sponge depicted in FIG. 20.
From this SEM micrograph, the presence of meso- and microporosity
in the calcium phosphate matrix is readily apparent.
Example 47
Implant Cages
[0208] A rectangular block approximately 1/4 inch.times.1/2
inch.times.3/4 inch was cut from a piece of damp (as removed from
the packaging) O-Cel-O.TM. cellulose sponge. This sponge piece was
trimmed as necessary so to completely fill the internal cavity of a
titanium nitride (TiN)-coated box-like spinal implant cage
(Stratech Medical, Inc.). The sponge insert was intentionally made
slightly oversized to ensure good fit and retention in the cage
assembly. The cellulose sponge block was fully imbibed with a
reactant solution prepared as described in Example 39. The
solution-saturated sponge insert was then inserted through the open
side of the spinal cage assembly and manipulated to completely fill
the interior cavity of the implant assembly. Despite the compliance
of the solution-saturated sponge, there was almost no penetration
of the sponge into the fenestrations of the implant. The
sponge-filled cage assembly, sitting on a Pt plate, was placed in a
laboratory oven preheated to 500.degree. C. and held at that
temperature for 1 hour. After cooling to room temperature, the
implant assembly was removed from the small amount of crusty white
solid resulting from reactant solution which had exuded from the
sponge insert and coated the surface of the implant. The TiN
coating on the cage appeared unaffected by the treatment, and the
internal chamber was filled with inorganic sponge material having a
mottled gray appearance. The filled cage assembly was refired at
800.degree. C. for 30 minutes in an attempt to eliminate residual
carbon from the inorganic sponge material. After cooling,
examination of the implant assembly revealed that the TiN coating
had been lost via oxidation, while the inorganic sponge material
was completely white. There was excellent retention of the
inorganic sponge material in the chamber of the spinal cage
assembly.
Example 48
Orthopaedic Implants
[0209] Two cylindrical plugs of approximately 3/8 inch diameter and
1/2 inch length were cut from a piece of damp (as removed from the
packaging) Marquis.TM. cellulose sponge (distributed by Fleming
Companies, Inc., Oklahoma City, Okla. 73126) using a hollow punch
(Michigan Industrial Tools, P.O. Box 88248, Kentwood, Mich. 49518)
of the appropriate size. These cellulose sponge plugs were then
trimmed to the necessary length so to completely fill the
bicompartmental central cavity of a 13 mm.times.20 mm
(diameter.times.length) BAK threaded cylindrical interbody implant
(SpineTech, Inc., 7375 Bush Lake Road, Minneapolis, Minn. 55439).
The plugs were intentionally made slightly oversized to ensure good
fit and retention in the two chambers of the titanium spinal fusion
cage assembly. The cylindrical sponge plugs were fully imbibed with
a reactant solution prepared as described in Example 39 and the
solution saturated sponge plugs were inserted through the open ends
of the spinal cage assembly and manipulated to completely fill both
of the internal chambers of the implant assembly. Despite the
compliance of the solution-saturated sponge, there was almost no
penetration of the sponge into the fenestrations of the implant.
The sponge-filled cage assembly sitting on a Pt plate was placed in
a laboratory oven preheated to 200.degree. C. Immediately, a
temperature ramp to 500.degree. C. was begun (duration of 16
minutes) followed by a 30 minute hold at 500.degree.. After cooling
to room temperature, the implant assembly was removed from the
small amount of crusty white solid resulting from reactant solution
which had exuded from the sponge pieces and coated the surface of
the implant. The titanium cage appeared unaffected by the
treatment, and the chambers were filled with inorganic sponge
material having a mottled gray appearance. The filled cage assembly
was refired at 700.degree. C. for 10 minutes in an attempt to
eliminate residual carbon from the inorganic sponge material. After
cooling, examination of the implant assembly revealed that the
surface of the titanium cage appeared to have undergone some
oxidation as evidenced by its roughened texture, while the
inorganic sponge material was white at the surface but still gray
at the center of the mass. Obviously, further heat treatment would
be necessary to fully oxidize the residual carbon in the interior
of the inorganic sponge masses in each chamber of the implant
assembly. There was excellent retention of the inorganic sponge
material in both of the chambers of the spinal cage assembly.
Example 49
Sterilization
[0210] Samples of gelatin-treated inorganic sponge material were
prepared as described in Example 46 and allowed to thoroughly dry
at room temperature for longer than one week. Pieces of this dry
gelatin-treated material were subjected to prolonged oven
treatments in an air atmosphere within a Vulcan model 3-550 oven
(see Example 39) to simulate conditions typically encountered in
"dry heat" sterilization procedures. The following table summarizes
these experiments:
17 Temperature (.degree. C.) Time (h) Observations 130 3 No color
change 130 6 Very slight yellowing 130 15 Very slight yellowing 150
4 Very slight yellowing 170 1 Very slight yellowing 170 3.5 Pale
yellow at surface, white interior
[0211] It was assumed that temperature equilibration between the
samples and the oven was rapidly attained due to the significant
porosity and low thermal mass of the materials. Clearly, there was
no significant degradation of the gelatin under these heat
treatment regimens. Furthermore, a subjective assessment of the
strength of these dry heat treated specimens showed no apparent
changes.
Example 50
Template Residues
[0212] A block of damp (as removed from the packaging) O-Cel-O.TM.
brand cellulose sponge with a weight of 7.374 g, setting on a
platinum plate, was placed into a Vulcan model 3-550 oven preheated
to 500.degree. C. and held at that temperature for 1 hour. At the
conclusion of the burnout cycle, 0.073 g of fluffy gray ash was
collected representing approximately 0.99 wt % of the original
cellulose sponge mass.
[0213] A block of damp (as removed from the packaging) MarquisTm
brand cellulose sponge with a weight of 31.089 g, setting on a
platinum plate, was placed into a Vulcan model 3-550 oven preheated
to 500.degree. C. and held at that temperature for 1 hour. At the
conclusion of the burnout cycle, 1.84 g of fluffy gray ash was
collected representing approximately 5.9 wt % of the original
cellulose sponge mass. An XRD pattern obtained from this ash
residue (FIG. 23) indicated the simultaneous presence of magnesium
oxide, MgO (major) (PDF 45-0946) and sodium chloride, NaCl (minor)
(PDF 05-0628) both phases resulting from the corresponding chloride
salts used in the manufacturing process of the cellulose sponge.
The presence of these two salts, in particular the MgO, may account
for the "incomplete" burnout of the inorganic sponge material at
500 to 800.degree. C. as noted in Examples 39, 41-44, 47, and
48.
[0214] Another block of the Marquis.TM. brand cellulose sponge was
extensively washed in deionized water by repetitive kneading and
multiple water exchanges. This thoroughly washed sponge was allowed
to dry in air at room temperature for two days, after which it was
cut into two blocks. The density of the washed and air-dried sponge
comprising each of these two blocks was calculated to be
approximately 1.03 g/inch.sup.3. Each of these blocks of washed and
air dried sponge was burned out according to the aforementioned
procedure. An insignificant amount of ash was collected from each
sample, indicating the efficacy of the washing procedure for
removing salt contaminants.
Example 51
Alternative Templates
[0215] A reactant solution was prepared as described in Example 39.
A variety of shapes, including disks, squares, and triangles, were
cut from a sheet of {fraction (3/32)} inch thick "Normandy
compressed sponge" (Spontex, Inc., P.O. Box 561, Santa Fe Pike,
Columbia, Tenn. 38402) using either scissors or hollow punches.
This compressed cellulose sponge is manufactured to have a smaller
median pore size and a narrower pore size distribution than either
of the commercially available household sponges (O-Cel-O.TM. or
Marquis.TM.) used in Examples 39-50. This compressed sponge also
has low ash levels (<0.1 wt % when burned out according to the
procedure mentioned in Example 50) indicating that it is washed
essentially free of salts during fabrication. The sponge is
compressed into a sheet which, upon rewetting, expands to restore
the original cellular sponge structure which, in the case of this
particular example, is approximately 1 inch thick. Imbibation of
water into the compressed sponge to saturation levels results in a
weight increase of approximately 28 times over the dry sponge
weight. The cut pieces of compressed sponge were fully imbibed with
the reactant solution after which they swelled to form cylinders,
cubes, and wedges. These solution saturated sponge articles,
setting on Pt plates, were placed into a Vulcan model 3-550 oven
preheated to 500.degree. C. and held at that temperature for 1
hour. After cooling, the inorganic sponge pieces were carefully
removed from the considerable amount of crusty white solid
resulting from the exudate material. All samples had been converted
to an inorganic replica of the original organic sponge structures.
The vestigial structures represented positive versions of the
original sponge structures with faithful replication of the
cellular elements and porosity. The vestigial masses were fragile
with very low apparent density, but they were robust enough to be
handled as coherent blocks of highly porous solid once they were
removed from the exudate material. The inorganic sponge material
was mottled gray, suggesting the presence of some residual carbon
in the structure. After refiring the samples at 800.degree. C.
(Vulcan furnace) for 15 minutes, the final inorganic sponge samples
were completely white. The integrity of the various samples made
from the controlled porosity cellulose sponge was improved over
corresponding samples prepared from the commercial cellulose sponge
materials.
[0216] FIG. 24 is a SEM of the Normandy compressed sponge expanded
in deionized water and prepared for microscopy as described in
Example 39.
Example 52
Modified Templates
[0217] Pieces of the inorganic sponge material from Example 51 were
immersed in a gelatin solution prepared as described in Example 46
except that 7.1 g of Knox gelatin was dissolved in 200 g deionized
water rather than 100 g of deionized water. The inorganic sponge
material readily imbibed the warm gelatin solution and, after
several minutes, the largely intact pieces of inorganic sponge
material were carefully removed from the solution and allowed to
cool and dry at room temperature. Significant additional strength
and improved handling properties were noted in the gelatin-treated
inorganic sponge material after the gelatin was allowed to
thoroughly dry for several days. The material exhibited
considerable improvement in compression strength and a dramatically
reduced tendency to shed particulate debris when cut with a knife
or fine-toothed saw.
[0218] Several pieces of gelatin treated sponge which had been
drying in air for >1 week were subjected to a burnout of the
organic material at 800.degree. C. (Vulcan furnace) for 30 minutes.
The snow white inorganic sponge samples were weighed after firing
and it was determined that the level of gelatin in the treated
samples was 13.8+/-1.0 wt % (with respect to the inorganic sponge
material).
[0219] FIG. 25 is a SEM of the air-dried gelatin treated inorganic
sponge which was prepared as described above. A comparison of this
SEM with that of the initial cellulose sponge material (FIG. 24)
shows how faithfully the sponge micro- and macrostructure has been
replicated in the polymer coated inorganic sponge material.
Example 53
Rewetting
[0220] Several pieces of air-dried gelatin-treated inorganic sponge
material from Example 46 were placed in deionized water to assess
the rewetting/rehydration behavior. Initially, the pieces floated
at the water surface but, after approximately 2 hours, the sponge
pieces began to float lower in the water indicating liquid uptake.
After 24 hours, the samples were still floating, but >50% of the
sponge volume was below the liquid surface. After 48 hours, the
inorganic sponge samples were completely submerged suggesting
complete rehydration of the gelatin and complete water ingress into
the structure via interconnected porosity.
Example 54
Shaped Calcium Phosphates
[0221] Several pieces of the inorganic sponge material from Example
39 were immersed in a 50 wt % solution of disodium glycerophosphate
hydrate prepared by dissolving 10.0 g
C.sub.3H.sub.7O.sub.6PNa.sub.2 (Sigma Chemical Co. reagent G-6501,
CAS # 154804-51-0), equivalent to 65.25 wt % as "Na.sub.2PO.sub.4",
in 10.0 g deionized water. The inorganic sponge material readily
imbibed the disodium glycerophosphate solution and, after several
minutes, the largely intact pieces of saturated inorganic sponge
material were carefully removed from the solution. The wetted
pieces, setting on a Pt plate, were placed in a Vulcan model 3-550
oven preheated to 150.degree. C. Immediately, a temperature ramp to
850.degree. C. was begun (duration of 50 minutes) followed by a 60
minute hold at 850.degree. C. After cooling to room temperature,
the surface of the treated inorganic sponge material had a glassy
appearance, and significant additional strength and improved
handling properties were noted. Upon examination of the pieces with
a Leica zoom stereo microscope, the presence of a glassy surface
was confirmed and rounding of the features was evident indicating
that some level of sintering had occurred. Considerable shrinkage
of the pieces was also noted.
[0222] An XRD pattern was obtained from a packed powder sample
prepared as described in Example 39. Peak analysis indicated the
solid to consist, in part, of Buchwaldite, sodium calcium
phosphate, NaCaPO.sub.4 (PDF 29-1193 and 29-1194).
Example 55
Discoid Bodies
[0223] A reactant solution was prepared as described in Example 39.
Disks were cut from a sheet of {fraction (3/32)} inch thick
Normandy compressed sponge using a 3/8 inch diameter hollow punch
and a model no. 3393 Carver hydraulic press (Carver Inc., 1569
Morris St., P.O. Box 544, Wabash, Ind. 46992) to ensure uniform
sizing. The disks were distended by immersion in deionized water
and the resulting sponge cylinders, each approximately 3/8 inch
diameter by 1 inch length, were then blotted on paper towel to
remove as much excess water as possible. The damp sponge cylinders
were then imbibed with approximately seven times their weight of
the reactant liquid. Nine of the solution imbibed pieces were
placed horizontally and spaced uniformly in a 100.times.20 mm Pyrex
petri dish. Two petri dishes, containing a total of 18 imbibed
sponge cylinders, were positioned in the center of the cavity of a
microwave oven (Hotpoint model no. RE963-001, Louisville, Ky.
40225) and the samples were irradiated at full power for a total of
two minutes. After 30 seconds of exposure, the microwave oven
cavity was full of NOx(g) and the reactant liquid which had exuded
from the sponge cylinders had reacted/dehydrated to form a crusty
white deposit in the petri dishes. The oven was opened to vent the
cavity, then full power irradiation was resumed. After another 30
seconds of exposure, the oven cavity was again full of NO.sub.x(g)
and steam. After venting the cavity once more, full power exposure
was resumed for an additional 60 seconds, after which the fully dry
sponge cylinders were removed. The sponge cylinders retained the
orange color of the original cellulose material and a considerable
fraction of the pores were filled with white solid. The pieces were
very robust at this point, there was little or no warpage or
slumping, and they could be handled and even abraded to shape the
pieces and to remove asperities and any adherent solid resulting
from the exuded liquid. The dried, solid-filled cylindrical sponge
pieces were arrayed in a rectangular alumina crucible (2-1/2"
W.times.6" L.times.1/2" D) and placed in a furnace preheated to
500.degree. C. The furnace temperature was ramped at 40.degree.
C./minute to 800.degree. C. and held at 800.degree. C. for 45
minutes. The resultant cylindrical white porous inorganic sponge
samples were robust and exhibited strengths qualitatively similar
to those attained from the fully dried gelatin-treated samples
prepared as described in Example 52.
[0224] An XRD pattern was obtained from a packed powder sample
prepared from the material fired at 800.degree. C. Peak analysis
indicated the solid to consist solely of whitlockite,
beta-Ca.sub.3(PO.sub.4).sub.2 (PDF 09-0169).
Example 56
Implantation of Calcium Phosphate Shaped Plug into Canine
Metaphyseal Bone
[0225] The porous calcium phosphate scaffolds, prepared as
described in Example 55, are instantly wetted by water, aqueous
solutions, alcohols, and other hydrophilic liquids in distinct
contrast to the gradual rewetting of the gelatin-treated scaffold
structure (Example 53). Blood readily wicks into the porous calcium
phosphate bodies without obvious detrimental effects. It is
believed that cells, e.g., fibroblasts, mesenchymal, stromal,
marrow, and stem cells, as well as protein-rich plasma and
combinations of the aforementioned cells can also be imbibed into
the porous structures.
[0226] Highly porous calcium phosphate cylindrical plugs were
prepared as described in Example 55 starting with 10 mm discs
punched from Normandy compressed sponge. The cylindrical porous
bodies were dry heat sterilized in DualPeel.TM. self seal pouches
(distributed by Allegiance Healthcare Corp., McGaw Park, Ill.
60085) at 125.degree. C. for 8 hours.
[0227] An animal experiment was initiated at Michigan State
University, whereby a 10.3 mm.times.25 mm defect was drilled into
the right shoulder (greater tubercle) of mongrel dogs. The site was
cleaned of bone fragments and the site filled with blood (and
marrow cells) as the site was centered in metaphyseal bone. The
scaffold implants were removed from their sterile pouch and
inserted into the defect site. Initial penetration to half of the
25 mm depth was easily achieved with little resistance. Slight
pushing was required to insert the remainder of the implant into
the-site, such that the top of the scaffold was flush with the
cortical bone surface. During insertion, blood could be seen
readily wicking up the porous scaffold. After complete insertion of
the implant, blood could be seen flowing throughout and around the
scaffold. The implant intergrity was maintained with no
fragmentation or breakage. The compatibility with blood and marrow
was evident. The surgical site was then closed.
[0228] FIG. 26 shows the cylindrical implant with initial wicking
of blood. FIG. 27 depicts implantation of the cylinder into the
canine bone.
Example 57
Porous Shaped Bodies of Hydroxyapatite
[0229] The mineral phase of human bone consists primarily of
compositionally modified, poorly crystalline hydroxyapatite,
Ca.sub.5(PO.sub.4).sub.3(OH). The hydroxyapatite crystallographic
structure is partially substituted by carbonate anions (7.4 wt. %)
as well as by metal cations present at fractional wt. % levels.
Analysis of human bone [R. Z. LeGeros, "Calcium Phosphates in Oral
Biology and Medicine," Monographs in Oral Science, Vol. (H. M.
Myers, Ed.), p 110, Karger Press (1991)] indicates, for example,
that the principal trace cationic constituents are as follows:
Na.sup.+ (0.9 wt. %), Mg.sup.2+ (0.72 wt. %), and Zn.sup.2+ (trace,
assumed as 0.05 wt. %). Heretofore, it has been difficult, if not
impossible, to synthesize hydroxyapatite mineral doped with cations
to the appropriate levels so as to approximate bone mineral. A
unique capability and distinct advantage of the RPR method is the
facile manner in which precursor solutions containing mixed metal
ions can be prepared and converted into solid phases via the redox
precipitation reaction and subsequent thermal processing.
[0230] A reactant solution was prepared by combining 7.88 g 50 wt.
% hypophosphorous acid, H.sub.3PO.sub.2, with 5.00 g deionized
water in a 250 ml Pyrex beaker. To this solution was added 22.51 g
calcium nitrate tetrahydrate salt, Ca(NO.sub.3).sub.2.4H.sub.2O;
plus 0.33 g sodium nitrate salt, NaNO.sub.3 (Fisher Certified ACS
reagent #S343-500, CAS #7631-99-4), equivalent to 27.05 wt. % Na;
plus 0.74 g magnesium nitrate hexahydrate salt,
Mg(NO.sub.3).sub.26H.sub.2O (Alfa/Aesar reagent #11564, CAS
13446-18-9), equivalent to 9.48 wt. % Mg; plus 0.046 g
Zn(NO.sub.3).sub.2.6H.sub.2O (ACS reagent, Aldrich Chemical Co.,
Inc. #22,873-7, CAS 10196-18-6), equivalent to 21.97 wt. % Zn.
Endothermic dissolution of the salts proceeded with stirring and
gradual warming on a laboratory hot plate to approximately
20.degree. C., eventually forming a homogeneous solution with a
water-like viscosity despite the high salt concentration. The
equivalent solids level (as cation substituted hydroxyapatite) was
27.39 wt. % and the target solid composition was 38.19 wt. % Ca,
0.90 wt. % Na, 0.70 wt. % Mg, 0.10 wt. % Zn, 56.72 wt. % P0.sub.4,
and 3.39 wt. % OH.
[0231] Eighteen 3/8-inch diameter.times.1-inch length cylinders of
Normandy sponge were imbibed with this reactant liquid to
approximately seven times their initial weight and microwave
processed as described in Example 55. The dried, solid-filled
cylindrical sponge pieces were then fired according to the
procedure described in Example 55. The resultant cylindrical white
porous inorganic scaffold samples were robust and subjectively
equivalent in strength to the articles produced in Example 55.
[0232] An XRD pattern, FIG. 28, was obtained, as described in
Example 39, from a packed powder sample of the material fired at
800.degree. C. Analysis of both peak position and relative
intensities over the angular range from 10 to 60 degrees (2-theta)
indicated the solid to consist of hydroxyapatite (PDF 09-0432).
Additionally, four unassigned peaks at 29.9, 31.3, 34.7, and 47.4
degrees (2-theta) were observed in this sample. These are,
presumably, due to the cationic substitutions leading to a
distorted hydroxyapatite lattice structure.
[0233] The inorganic porous material prepared in Examples 39
through 57, derived from the precursor aqueous solutions involving
the minerals or materials described in the preceding Examples 1
though 38, can be utilized in a variety of applications. These
applications include, but are not limited to: bone or teeth
replacement, filters, catalytic converters, catalytic substrates,
bioseparations media, pharmaceutical excipients, gas scrubber
media, piezoelectric ceramics, pharmaceutical drug delivery
systems, or aerators. As the examples illustrate, the composition
can be easily tailored to accommodate the particular end use
without the concerns of extensive material preparation such as
purification or particle size treatment. Further, the porous
inorganic material can be formed into a variety of practical shapes
without elaborate tools or machining. The present invention may be
embodied in other specific forms without departing from the spirit
or essential attributes thereof and, accordingly, reference should
be made to the appended claims rather than to the foregoing
specifications, as indicating the scope of the invention.
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